HU227453B1 - Hiv replication inhibiting pyrimidines, and pharmaceutical compositions containing them - Google Patents

Description

Field of the Invention The present invention relates to the use of plrinidis stem cells for the manufacture of a pharmaceutical composition for inhibiting the proliferation of human immunodeficiency virus (FL), and to novel pyrimidine derivatives, pharmaceutical compositions thereof, and pharmaceutical compositions containing the novel compounds.

The I) European Patent No. 834507 a substituted áamri.no- ^{:, 3,5-triazl'n derivatives as capable of inhibiting proliferation of HIV. The compounds of the present invention differ in their structure as well as in their superior inhibitory activity against HIVV.

All of them are 945,442, which in European Patent 0 945 443 reproduce HVR proliferation. substituted pyrimidine derivatives having inhibitory activity. The invention series! Compounds differ from the compounds disclosed herein in the structure of the substituents on the pyrimidine ring,

International Patent Publication No. WO8 / 8/41512 discloses substituted 2-aminopyrmitrin moieties and their selective inhibitory action on protein kinases.

European Patent Application No. t, 135,472. microbicidal derivatives of NC- (2-tert-butyl) -2-tin: toopyrin;

WO 95/10506 discloses IN-alkyl-N-tarrylpyrimidine derivatives and derivatives thereof, and their use in inhibiting circricotropin release.

The present invention is a general picture (1)

R

compounds, their N-oxides, pharmaceutically acceptable addition salts, quaternary ammon derivatives and stereochemically isomeric forms thereof, for use in the manufacture of a medicament for the treatment of HIV (human immunodeficiency virus) infection. In the formula (a), a is a value of δ, 1,2,3,4 or 5;

R ⁵ is hydrogen; Chapter; CHO; alkyl having 1 to 6 carbon atoms in the alkyl moiety; C 1-6 alkyl; the elbows. alkoxy carbonyl containing from 1 to 6 carbon atoms; formyl, alkylcycloalkyl having 1 to 6 carbon atoms in the alkyl moiety, alkoxycarbonyl having 1 to 6 carbon atoms in the alkyl moiety, or alkylcarbonyloxy having 1 to 6 carbon atoms in the alkyl moiety. C 1 -C 6 alkyl; or the alkyl moiety is substituted by an alkoxyalkyl radical containing from 1 to 6 carbon atoms, the alkoxyalkyl carboxylic moiety having 1 to 12 carbon atoms in the subunit moieties: and each R ^{2 is} independently halogen; hydroxy, cyano or-C <~ O) R ⁶ - group of general formula adott.esetben szabszfitóált tartetaazó 1-6 carbon-alkyl; C 3-7 'carbon atoms94143-3689 MR / JG Mazo cycloalkylated; one or more of the leftgene &quot; totmmls or cyano groups optionally submerged by C2-C6 alkyl groups. alkynyl containing from 2 to 6 carbon atoms optionally substituted with one or more hexogens or parent moieties; C 1-6 alkoxy; an alkoxycarbonyl group containing from 1 to 6 carbon atoms in the moiety; karboxtfcsoportot; cyano-grouped nitro rain; ambtocsöportoi; a mono or di (C 1-6 alkyl) alkyl moiety; pehliaiegénatetilcsoportot; polyethylene lihaiogénmetoxiesoportoi; pol MogénmetÖtíoesoportot; or -S (O) p R ^ t ~ MH-S (-O) _p R ⁶ -; -C (-O) R ⁶ -: -NHC (== O) H; -C (-O) KHNH ₂ -; NHC = {o0; -C (-NH) R ⁶ 'or (c)

and in each of the latter formulas, A is independently selected from the group consisting of mtogen atom or tnetinesophor or CRO group and M group B or oxygen or sulfur; or -NR <4>;

p is 1 or 2; and

R * is methyl, amino, mono- or dimethylatnino or polyhalogenomethyl;

L is C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or C 3 -C 7 alkoxy, each of these aliphatic groups being optionally substituted. with 1 or 2 substituents selected from each other:

Eicfealkifesopyr containing 3 to 7 carbon atoms;

iadol-1 'or isophedotyl, each optionally substituted by one, two, three or four substituents independently selected from 1 to 6 carbon atoms or alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms. , -cyano ···, aminocarfeosyl, nitro, amino, polybalogenethyl, polyhatogenetnethoxy or alkyl having 1 to 6 carbon atoms in the alkyl moiety;

* a phenyl, pyridyl, pyridinyl, pyrazinyl or pyridazinyl group, each of which aromatic rings may be optionally substituted with one, three, four or five substituents. and independently selected from the meaning given by R ^. azabszdtaensekksil; obsession

L is -X-R * wherein

^R5 feoil-, piriöinil-, pirtnöólmt-, pyrazinyl or piridazínifesoport which the aromatic rings optionally .mindegyike szubsztttoálva be one, regardless of two bars, or in four substituents each selected from a specified meaning of R ^ and szahsztítoensekkeh

X is ^NR -NH-NH-, -N + N-, - &gt; -C (O) -, -CHOH-, -S-, -S (= Oj- or -S ') ₂ -;

Q is hydrogen or halo, or C 1-6 alkyl, polyhalo (C 1-6 alkyl) or -NR ⁴ R ³ halo;

Ro and R ⁵ are independently hydrogen or bidroxi-, alkyl having 1-12 carbon atoms, an alkoxy group having 1 to 12 carbon atoms, alkiikatfeonil- containing I to 12 carbon atoms in the plecoptera, the. alkyl moiety in alkylcodecarbonyl, aryl, amino, alkyl moieties or aliphatic moieties having from 1 to 12 carbon atoms. Mono- or dialkylamino containing 1 to 12 carbon atoms or mono- or dialkyl-8m.i.-mono- or dialkyl-8m.i. containing 1 to 12 carbon atoms in the alkyl moiety or alkyl moieties | Illustrious. mimsUstt in said ancestors of the above-mentioned 1-12 carbon atoms, one or two of the substituents selected from the group consisting of hydroxy, C 1-6 -alkoxy, C 1-6 -alkoxy, C 1-6 -alkoxy, carboxy; 6-carbon alkoxybutyl, cyano, amino, Imlino, alkyl, or aliphatic moieties containing from 1 to 6 carbon atoms, mono- or diphthalnino, polyhalogenethoxy, polyhalogenemethoxy, polydalogemethyl. -S (~ OjpR. ⁰ , -NH-S (~ O} ₄₎ R ^f \ -C ("Ö} R. '',

Among -CMWíbiiU NHC <O> ^ R, -C (-NH} ^R6, aryl and Het groups may be substituted selected sztíbszötoenssel; or

Rz and ^R5 together pimslidtól · ·, pipettes »- tsorfelinil-, azido or mono-or <6 (of 1 to 12 carbon OCF) alkilaau« o- (l-4 carbon atoms in the & tartalmazólalkiSáénesöportot otnak:

Y is halogen; hydroxy; C3-C7 cycloalkyl; a carbonyl group containing from 2 to 6 carbon atoms optionally substituted with one or more balogens; primes 2 to 6 carbon atoms: substituted with 1 to 6 carbon atoms substituted with cyano or -C ⁰ -OIR ⁰ ; C 1-6 alkoxy; alkoxy carbohydrate moieties having 1-6 carbon atoms in the alkyl moiety; ksrboxilesoport; cyano: nitro; aminocseport; mono or dialkylamoylcoated carbon mono or dialkylamoyloxy carbonyl moiety; pöiíhaiogénmetoxiosopört; polsMogénmetötíocsoport; -SAöSpR ^6; -NH-S (-O) p R ⁶ -C (-O) R ⁶ ; -NHC (-O>H; -C (-O) NHNH 2); • NiCt-OiR ⁶ ; -C (-NH) R ^fe or aryl;

aryl is phenyl or one, two, four, five or five spacers independently selected from balogen, C 1-6 alkyl, C 3-7 C 1-10 alkoxy, C 1-6 alkoxy, C 1-6 alkyl, thio group; Phenyl substituted with 6 carbon atoms or with a polyhaloalkoxy moiety having 1 to 6 carbon atoms in the alkoxy moiety; and

Seven represents an aliphatic or aromatic theero radical, such as the aliphatic heterocyclic group may be pyrrolidinyl, piperidyl, dimethylmimethyl, piperazinyl, morpholymethyl, tetraindrofutanyl or tetrahydrothio; and said aromatic heterocyclic moiety may be pyrrolyl, femnyl, ttenyl, spinyl, plinidinidine, pyruzinyl, or pyridine moiety, each of which aromatic heterocyclic groups may be optionally substituted by hydroxy.

The invention further provides. az: new compounds of formula I-a

CM 'refers to their N-oxides, addition salts, quaternary maize derivatives and stereochemically: isomeric forms thereof In the formula (I-a), q is δ, L 2, 3 or 4;

♦ ♦ ♦ fc * ♦ ♦ fcfc y «« fc * * · »

R * is k-cogene; Chapter; fertnsktsoport; an alkylcarbyl group having 1 to 6 carbon atoms in the alkyl moiety; An alkyl group containing from 1 to 6 carbon atoms; a needle carbonyl group containing 1 to 6 carbon atoms in the alkyl moiety; ion, alkylcarbonyl having 1 to 6 carbon atoms in the alkyl moiety, az. alkoxycarbenyl containing 1 to 6 carbon atoms in the alkyl group or alkyl having from 1 to 6 carbon atoms in the alkyl moiety; nboruloxy group substituted with 1 to 6 carbon atoms; or an alkoxyalkyl-alkonyloxy group substituted with a (1-6C) alkoxycarbonyl group containing from 1 to 6 carbon atoms in the alkyl moiety;

R ^is cyano, atninokarbenífesopöft, mono- or dimeíilamiookarbondcsopori, or cyano, or ammokathenil- -nono- disnetlknninokarbosilcsoportiai or substituted with C1-6 alkyl taxtalmazó alkilcsopoxt, alkenyl or substituted eianocsoportíal · 2-6 carbon atoms having 2-6 carbon atoms cyano sznbszíituáii alkimlcsoport;

each R is independently halogen; OH; C 1 -C 6 alkyl substituted with cyano or -O (-O) -CH 2 -; 3 to 7 carbon atoms containing cifcycloalkyl; alkenyl having from 2 to 6 carbon atoms optionally substituted with one or more balogenates or cyano; one or more optionally substituted szafeszlrteáít eiaxtocsoporttal haiogéogtommal or 2-6 atoms containing ¹ · alkiniiesoportot; Alkoxy groups containing from 1 to 6 carbon atoms; alkoxycarbonyl having 1 to 6 carbon atoms in the alkyl moiety; katboxiicsoportot; eiáísocsoportot; mtrocsepörtoí; amino; mono- or di- (containing t-6 carbon atoms) alkyl; polihalogérttnetilesoportoi; poiiliaiogéntsetoxlcsoportot; poíihalogénmetilttocsoportot; or -NH-ShO 1 ^ R ⁶ ; -C (-O) &lt; ⁶ &^gt;. NHC (= O) R; -C << WIN ₂ ; -NHC (O) R ⁶ ; -C (-W) R ⁶ ; or (c); and each A in the latter formula is independently an halogen atom or a methine group or a GR ^{, <?} general formula group and

S is a nino group or an oxygen or sulfur atom or a group -NR ⁿ ;

p is Ϊ or 2; and

^Ö R is methyl, amino, or rnoao- dtmetiíatnlno- or polihafogénmetifesoport; '

I is C 1-10 -alkyl, C 2 -C 11 -alkenyl, C 2 -C 5 -alkynyl or C 3 -C 7 -cycloalkyl, each of said aliphatic groups being optionally substituted as follows with independently selected I or 2 substituents:

* C3-7alkyl;

♦ swept indolyl or isoindolyl, each optionally substituted with one. with two, three or four carbon atoms selected independently from each other by a balogen atom or an alkyl, hydroxy, C 1-6 alkoxy, cyano, anthocarboxymethyl, nitro, acoustic, polyhalemethyl, polyhalomethoxy containing from 1 to 6 carbon atoms or an alpha-carbohydrate moiety having 1 to 6 carbon atoms in the alkyl moiety;

«Χ« «« «* fe« .íl-, piridkát-, pirimídimk pírazmü- or pindázihilesöpört which aromatic rings are each, may be optionally substituted with one, two, bars or four or five independently szufesztítetssel selected from each R ² is selected for reporting specified substituents; obsession

L is -X-R-, OH

R? is selected from the group consisting of textile, pyridyl, pyrimidinyl, plrazinyl, and pyridazutyl, each of which may optionally be substituted with one, two, bar, four or five substituents selected from the group consisting of mggedeonl as RX; and

X is -NR * -, -NM-NH-, -Ν ^::: Ν-, -O-, -C (~ ^: <) -, -CHOH-, -S-, or -8 (-O). ) 7;

is hydrogen, halogen, alkyl of 1 to 6 carbon atoms, potassium (carbon at 1) or -Nte * R-, and

R ⁴ and R ⁵ are, respectively, hydrogen or hydroxy, alkyl having 1 to 12 carbon atoms, alkoxy having 1 to 12 carbon atoms, alkyl having 1 to 12 carbon atoms on the alkyl moiety, alkoxy-carbonyl having 1 to 12 carbon atoms in the shade. -, amino, mono or di-carbonyl containing 1 to 12 carbon atoms in the alkyl moiety or dummy, or mono- or di-alkylamines containing 1 to 12 carbon atoms in the alkyl moiety or alkyl moieties, each of which optionally contains 1 to 12 carbon atoms unbranched with one or two substituents selected from hydroxy, C 1-6 alkoxy, C 1-6 hydroxyalkoxy, carboxy, C 1-6 alkoxycarboyl, cyano, amino, banno, the alkyl moiety or alkyloxy moiety containing 1-6 carbon atoms, mono- or dialkylarone, polyhalogen, polyhalo oxy, pokhaiogén-neíikio-, -S (- = 0) ^ \ -Níí StbOiptŐS-C ^(: O) R.. ⁶ -., -NHC (= O) H, -C (-O) NHNH ₂ -, -NHC (-O) R ⁶ -, -C (-N 1) R ⁶ -, aryl and ϊ-let. substituted with a substituent selected from the group; obsession

R ⁴ and R * together form a alkylideneidene group containing pyrrolidinyl, pyridinedis, mortocail, then mono- or di (C 1 -C 12) -alkylammonioyl-d containing:

Y is -halogen; hydroxy; Eictoalkyl group containing 3 to 7 carbon atoms; alkenyl containing from 2 to 6 carbon atoms, optionally sto-sulfilated with one or more halogen atoms; an alkyryl group containing from 2 to 6 carbon atoms optionally sulfated with one or more halogen atoms; alkyl having 1 to 6 carbon atoms as cyano or -C (- O) R &lt; 2 &gt; Pseudohexa containing from 1 to 6 carbon atoms; the alkyl moiety is a &lt; RTI ID = 0.0 &gt; oxy < / RTI &gt;carboxy;eiaaocsopöit;nittocsoport; • amineesöport .; in the subunit or alkyl moieties. A mono- or dialkylamino group containing from 1 to 6 carbon atoms; poisfeaiogénmetitesoport; potíhalogénmetoxtesöport ';polihalogénmetikíoösoport; -S {= · <) ipR ⁶ -; -NH-S (= O -? R ⁶ -; .f (<}) R ⁶ -; -NIC 1 O 10 H-; -C (-O) NHNH ₂ -;

-NHC (= O) R ⁶ -; C (= NH) R ⁶ ; or an arite group;

aryl is -phenyl or egv, two, three, four or five substituents independently selected from halo, halo, C 1-6 -alkyl, C 3-7 -cycloalkyl, nitro, C 1-6 -alkoxy, and C 1-6 -alkoxy. a phenyl radical substituted with a carbon monoxide having 1 to 6 carbon atoms in the alkyl moiety, or: a polyhalogenated &lt; RTI ID = 0.0 &gt; &lt; / RTI &gt; and

Bet is an aliphatic or aromatic heterocyclic group, wherein the aliphatic heterocyclic group is pyrrolidinyl. piperidityl, homppiperidinyl, piperazinyl. morpholinyl. tetrahydrofural- or tetpalaryl-thienyl ♦ ♦

X Η Jf k k · ♦ »» »mely s *» »» »» »» »» »» »» »» »» »» »» s each of which may be substituted by an oxo group; and said aromatic heterocyclic group is selected from the group consisting of pyridyl, furartyl, tetal, pyridhul, pinmidarul, pyrazinyl, and pyriduzhnl (each of which is substituted on its respective ancestors by a hydroxy group.

As used herein, the term "1-6 carbon atoms", whether alone or as part of another group, refers to straight or branched chain saturated hydrocarbon groups containing from 1 to 6 carbon atoms, such as methyl. ethyl, propyl, 1-methyl-methyl, methyl, pentyl, hexyl, 2-methylpropyl or 2-methyl-1-yl; straight or branched under the alkyl groups containing 1 to 10 carbon atoms, either as a single group or as part of another group. Saturated hydrocarbon radicals having from 1 to 10 carbon atoms, such as those listed in the alpha group containing from 1 to 6 carbon atoms, and the imaging, octyl, yl or decyl radicals; the

C 1 -C 12 alkyl groups. is used, either alone or as part of another group, in the definition of straight or branched chain hydrocarbyl groups containing 1 to 2 carbon atoms, such as alkyl groups having 1 to 10 carbon atoms. the foregoing groups, or the anaecyl or dorfecyl moiety under a C 1-4 alkylidene moiety, have a straight or branched chain saturated C 1-4 saturated hydrocarbon moiety, such as methylene, 1,2-alkenyl, or 1,2 -ethyl ether, 1,3-propanediyl or 1,3-propylidene or 1,4-butanediyl or 1,4-phyllethyldiphthyl; under cycloalkyl groups containing from 3 to 7 carbon atoms, cyclopropyl, cyclophenyl, cycloppenyl, cyclohexyl, and cycloheptyl; beneath the C2-6alkyl groups there are straight or branched chain hydrocarbon esoparticles containing 2 to 6 carbon atoms and a curing agent. for example, stenyl, propenyl, feuteuyl, pentenyl or texenyl; the

Examples of C2-C10-alkemyl groups include straight or branched chain hydrocarbon groups having 2 to 16 carbon atoms and double-alkoxy groups, such as those of the C2-C6-alkemyl groups, and also the groups I, O, O, N, and N; ; straight or branched chain hydrocarbon radicals having from 2 to 6 carbon atoms and C2 to C10 alkynyl groups and straight or branched chain hydrocarbon groups having from 2 to 6 carbon atoms and backbone bonds, such as alkenyl, propyl, methyl, pentynyl or hexynyl; branched hydrocarbyl groups having from 2 to 16 carbon atoms and triple carbon atoms, such as those referred to in the dictionation of C2-C6 alkynyl moieties or the heptinyl, octynyl, nouinyl or dememe groups.

In the context of substitution snow, the term refers to a carbonyl group when attached to a carbon atom; a sulfoxide group if it is attached to a latex and a sulfone sulfate when it is attached twice to a sulfur atom,

The term halogen means fluorine, chlorine, bromine and iodine. As used herein, and hereinafter, the polyhalogen methyl group is a group or moiety which is a methyl group substituted by one or more halogen atoms, more particularly a methyl group substituted by one or more fluorine atoms, e.g. or a group noodle wherein the alkyl group containing 1 to 6 carbon atoms is singly or multiply substituted by a telogen atom, such as a halo group or a group II-diS orethyl group. When an alkyl group is attached more than one telogenically within the meaning of the polyhalomethyl group or the polyhaloalkyl group containing the alkyl moiety-6 isomer, then these halogen atoms may be the same or different.

*: ♦

The term "Bet" is almi. the heterocyclic groups mentioned in the Seven Dettnellions include the possible isonitrile nucleus of the bacta, such as the pyrrolyl group; · include SB-psnobl groups,

Beesopone is bonded to the remainder of the molecules of formula (I) or (hair) via a carbon atom or a heteroatom such as the tolerocyclic pyridine moiety, which may be 2-pyridyl, 3-ptoate, or d-psyridyl.

If any variable substituent (for example, aryl group, R ^z or &b> multiple salts occurs once in any part of the molecule), each of its values may be mutually exclusive.

Lines introduced from each substituent into the interior of the gingival systems suggest that the particular bond may be attached to the femur of the respective ring fragments.

It will be understood by one of ordinary skill in the art that any of the compounds of formula (I) or (I-a) of the present invention, as well as their N-oxides, addition salts, quaternary amx derivatives and stereochemically isomeric forms may include one or more stereochemically isomeric forms.

The term "stereochemistry isomeric horseradish" as used herein denotes all such talented steroidal amines in which the compounds of formula (I) or (1-aj) and their N-oxide salts, addition salts, quaternary amis derivatives are described. Unless otherwise sworn, the chemical designation of the compound in question is a mixture of all possible stereochemically isomeric forms, such mixtures may contain all possible trans-stereoisomers and the individual monomer of the basic structure of the molecule. The compounds of the general formula (I) or '(ia), and their N-oxides, salts, solvates or quaternary smm derivatives are substantially free of the other isomeric form, i.e. less than 20%, more preferably less like 5%, closer to less, throne 2% and most preferably containing less than 1% of other isomers, more particularly the stereogenic centers may be R- or S-co-initiating; and the sub-substituents attached to the (partially) saturated bivalent ring may be cis- or trans-conurable. Compounds containing a double bond may have E or Z stereochemistry with respect to this double bond. It will be understood by those skilled in the art that compounds of formula (I) or (ϊ-a) are obviously within the scope of the present invention. stereochemically isomeric forms.

For therapeutic use, salts of the compounds of formula (I) or (I-a) wherein the salt-forming ion is pharmaceutically acceptable. We can, however, make use of it. salts with unacceptable acids and bases, e.g. for the preparation or purification of pharmaceutically acceptable compounds. Thus, it will be understood by one skilled in the art. and pharmaceutically acceptable and non-pharmaceutically acceptable salts are included within the scope of the invention.

Thus, the above-mentioned addition salts with pharmaceutically acceptable acids and bases are such salts that are therapeutically effective, non-toxic, or prepared with such acids and bases from compounds of formula (Ϊ) or (I-a) which are susceptible to salt formation. Pharmaceutically acceptable acid addition salts can be readily prepared by treating the corresponding free base form with a suitable acid, for example, inorganic acids such as halogenated hydrocarbons (e.g., mydrogen chloride or hydrogen chloride), sulfuric acid, nitric acid or phosphoric acid, e.g. , propionic acid, bidroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e. ethanecarboxylic) acid, malonic acid, (i. snnsu & iisavai or pamoic acid.

obviously - can these salts be treated with a suitable base? they can be converted to the free base form.

Compounds containing the acidic proton (Formula I or I) can be converted to the appropriate non-toxic fatty salts or amines by treatment with a suitable organic or inorganic base. examples of such basic salts include ammonium salts; alkali and alkaline earth salts such as lithium. sodium, potassium, magnesium and calcium salts; with organic bases. for example, benzane, N-meb: I-D-glycine mln5s; or hydrabaminal formed salts; -and amino acids, for example! arginhme.1 or llzhxael trained, salts.

By "addition salt" is meant also solvates of the compounds of general formula (I) or (I-a) and their salts. Examples of such solvents include hydrates and alkobolates.

Some of the compounds of general formula (I) or (ii-a) may also exist in the tannomeric form. While no express reference is made to such forms, those skilled in the art will appreciate that they are intended to be embraced within the scope of the invention.

In the following, the term "compounds of formula (III) or" compounds of formula (I) "is intended to include not only these compounds, but also their quaternary αm derivatives, their pharmaceutically acceptable acid addition salts: and all possible stereoisomeric forms thereof

A specific group of compounds of formula (I) are those wherein R * is hydrogen or aryl (boiled) -, C 1-6 -alkylcafeoml, C 1-6 -alkyl, C 1-6 -alkyl; C 1-6 -alkyl substituted with C 1-6 -alkoxycarbonyl or formyl, C 1-6 -alkylcarboxy, or alkoxy-C 1-6 -alkoxycarboxyl.

A further specific class of compounds of formula (I) is one in which one or more of the following restrictions apply:

^i)} R is hydrogen;

(ii) n values;

iii) R is cyano, preferably ^NR - in a para-group relative to the group;

iv) Y is cyano, -CfeO 1 NH 2 or a balogen atom, preferably a halogen atom;

v) Q is hydrogen. or -NREs? wherein R ⁴ and R ^{6 are} the latter; preferably hydrogen;

vi) L is. -X-K-, where X is preferably -N'R ^} or an oxygen or sulfur atom, particularly preferably X is an imo group, and R- is a substituted phenyl group, with preferred succulents being balogene, ciam and Alkyl groups containing -6 carbon atoms.

Another special group of compounds of formula (ϊ-a) are those wherein ^R! is hydrogen or aryl, oxymethyl, the alkyl moiety contains alkylcatboyl containing 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms, alkoxycarboyl or fertynyl having 1 to 6 carbon atoms in the alkyl moiety, or azobutyl having 1 to 6 carbon atoms in the dummy part. a alkyl group containing 1 to 6 carbon atoms substituted by an alkoxycarboxy group containing from 1 to 6 carbon atoms.

* Φ

Another specific class of compounds of Formula ü-a is compounds for which one or more of the following restrictions apply:

i) q is δ;

ü) R ^a is cyano or -O (-0) 01¾, preferably R ^a is cyano;

iii) Y is cyano or -CO3 / NH2O or halo, preferably halo; arc) Q is hydrogen or -NR ⁴ -? wherein R ⁴ and R '' are preferably hydrogen

v) L is -XR-, wherein X is preferably -NR1 or oxygen or sulfur, particularly preferably X is -imino, and R- is a substituted phenyl group, with the preferred substituents being halogénafomok. and C 1 -C 10 alkyl groups.

An interesting group of compounds of formula 0) or 0-a) are those wherein L is -XR 'wherein R' is phenyl substituted in the 2-, 4- and 6- positions, these substituents independently selected from the group consisting of chlorine, bromine, or pteocnoms, or cyano or C 1-4 alkyl moieties.

Also of interest are compounds of formula (I) or (I-a) wherein Y is chlorine or chromium and Q is hydrogen or amino.

Of particular interest are those compounds of formula (I) or (I-a) in which the pyrimidine

2 helyzeiében. related group sgy 4-cáanoaaili'nocsopOJrt.

Preference is given to compounds of formula (Ia) or (Ia) in which a 4-cyanoanilino group is attached at the 2-position of the piperidine ring, L is a group of the formula -XR? tri-substituted phenyl, Y is halogen and Q is hydrogen or amine;

The most preferred are the. The compounds listed below and their X-oxide, pharmaceutically acceptable addition salts, quaternary amine derivatives and stereochemically isomeric forms thereof

4-f (4-3 '5Íoo ki.ör-5-O - [(2,4,6-trtj «eíilfe Nil) famH o)' - 2-pyrimidinyl« yl] íímlíioj: -bertZíWtrlh

4 - ((S-chloro-4 - ({2,4, .delta trtmetiífex5íl) aaJim] -2-Pixie "Dini] amino} ben2om- {nk

4 - ({5-bromo-4- (4-CIMTIG ~ 2, O-danehíienoxi) -2-pi'rín) idiniíjatmno] benzoate »ik

4-f [4-I; roitto ~ 5 ~ chloro-6-f4-cyano «« - 2,6-rtimertífenil) amrtm} -2 ~ pinmidimll "miso-huh" ZOS "rik

-4-jj5-br6rti-6 - (!! (4-EIA K> -2,6-dhrteíiifcmí) 3 «« i o) -2-pirsmídmd) am thio] -beHzoí «tr l,!

4 - [(4-AMIS-5-chloro-o '<4-cyano-2 _r h = -dÍmetilfeönoxi) -2 ~ ptrímidimíjamino] - in »zonitrtl; and

4 - [[4-amio-bromo-5-O- (4-cyano «o-2, 6 - di« ist .li'eniioxi) -2-pyrimido "has been reported« Noj beHzon3ir-l £!.

In general, the compound of formula (ia) may be prepared as a bed to form an intermediate of formula (11) wherein W ^! is a suitable leaving group, such as a halogen atom, or a hydroxy, sulfate, lysate, thiomethyl, methanesulfonyl or triuernosilyl, side-chain reaction, with an amino compound of formula (111), optionally in solvent-free conditions or against reactants. in an inert solvent such as ethanol, l-tucyl-2-pyrrolyl-lB 3, N, N-diarylformamide, 1,4-dioxane, tetrahydrofuran, dinethylsulfoxide, ladders, volatiles, e.g. or under a nitrogen atmosphere and

X * optionally in the presence of an acid such as 1 N hydrochloric acid in diethyl ether at temperatures between 50 ° C and 250 T

(Π1; Π1)

The reaction trees described in this reaction and in the following; the reaction products may be isolated from the reaction mixture and, if required, further distilled from my-branch offices by methods well known in the art, such as exiracation, crystallization, distillation, trituration and chronography.

L is -NR ^! -the general formula. having the following group (Ia) Compounds of formula I, e.g., (1-al} compounds eíőállíthatók by reacting the compound (IV) köztiíewéket formula -. wherein W ^z is a suitable leaving group such as a hatogénatom or tríftáícsoport - a < Intermediate V is reacted under solvent conditions. or in a suitable solvent such as ethanol, 1-methyl-1-pyrrolidiazole, N-dinethylbimethylene, 1,4-dioxoxane, teirahldrofarane, dimethylsulfoxia, lennlinba, sulphate or acetone, inert to oxygen, e.g. optionally in the presence of an acid such as 1 N hydrochloric acid in diethyl ether at temperatures close to 50 ° C and 25 ^° C.

II-A-i5

Compounds of formula (I-a), wherein I is -O-E.-, are compounds of formula (I-a-2). They may be prepared by reacting an intermediate of formula (IV) wherein: is a suitable leaving group, e.g. a halogen atom or a triaryl group - is reacted with an intermediate of formula VI in a suitable solvent such as 1,4-dioxane bao, dimethylbultoxide, tetrallane or sulfolane in an inert atmosphere of reactants, e.g. in the presence of sodium hydride, potassium dihydride or sodium hydroxide at temperatures between 50 ° C and 25% by weight.

Q

The compounds of formula (I-a) can also be prepared by converting the compounds of formula (I-a) into each other by methods well known for the conversion of functional groups.

♦ «*« «**; * ♦ φ *« Φ * * «* * * Φ

X * ΦΦΦ »ΧΧ

The compounds of formula (Ia) may be converted to the corresponding N-oxides by converting nitrogen from the nitrogen to the N-oxide by any of the methods well known in the art. Reactions for the preparation of N-oxides are generally carried out by treating the starting compound of the general formula (Ia) with a suitable organic or inorganic peroxide. Examples of suitable inorganic peroxides include hhfco «enpe.rox. alkali metal or alkali disodium peroxides, such as sodium or potassium peroxide; however, organic peroxides which may be used for this purpose include, for example, snegendhltelyl: peroxy acids such as beazolecarboperoxocarboxylic acid or benzenecarboperoxosubstituted with heptogen; For example, 3-chlorobenzoylsorbic acid is further peroxycalkanecarboxylic acids such as peroxoacetic acid; and alkyl-bis-hydroxy peroxides, such as cerebnylbihydroperoxide. Suitable reaction solvents include, for example, water; lower carbon alcohols such as ethanol; Hydrogen sulfide, such as toluene; ketones, such as 2-butanone; halogenated hydrocarbons, such as dichlorotransstane; and mentions: mixed solvents such as compounds of formula (Ia) having a balogene atom in which Q is substituted at the Q position. -MR ⁴ H (for the radicals 1-a 1) using a compound of formula NH-R ⁴ as a reagent for this purpose, in an inert solvent such as 1,4-dloxanepean, optionally in a suitable base, e.g. or in the presence of NIN-diisopropylethylamine If the hydroxyl group contains ?, it may be convenient to carry out the reaction below: a) by protecting the appropriate compound NH> R ⁴ , i.e., a horseradish with a suitable protecting group such as trialkylsilazole. Following the reaction, the protecting group may be removed from the art by methods well known in the art.

Some of the compounds of formula (I-a), as well as some of the distillate products useful in carrying out the processes of the invention, may contain asymmetric carbon atoms. The stereochemically pure forms of such compounds and intermediates may be prepared by methods well known in the art. Thus, for example, the salsaxis swarms could be separated by physical means, such as selective crystallization or chromatography, such as countercurrent partitioning or shell chromation. The cantiantiomers may be prepared from the appropriate racemic mixture by first converting the racemic flame into a mixture of diastereomeric salts or compounds with a suitable resolving fiber, such as a chiral acid; the dastereroomers. or mixtures of the compounds so obtained are then subjected to physical separation, such as selective crystallization or chromatographic separation, such as by flash chromatography; and finally converting the individual transomeric salts or compounds to the corresponding enalomers. Pure stereochemically isomeric forms may also be obtained from the pure stereochemically isomeric forms of the corresponding intermediates and starting materials, provided that the reactions which occur are stereospecific.

An alternative method of separating the compounds of formula (I-a) from the enantiomeric form is by flash chromatography, in particular by chiral stationary phase chromatography. The same method can be applied to the corresponding communication products.

Part of the intermediates and starting compounds used in the process of the invention are known compounds and are commercially available or may be prepared by methods well known in the art.

Is L in place of -XR? a radical of formula (11) compounds of formula, i.e., (II-1) compounds can be prepared by reacting the compound (VI1) piriraidm-szánuazékot formula: - wherein each ^W! is as previously defined - reacting a compound of formula (VIII) with reactants in the presence of a "base" such as triethylamine or N, N-diisopropylethylamine in an "inert solvent" such as 1, 4-dioxanebau or 2-propanol; . Distinct regiospelic isomers: formed, they can be separated by appropriate separation techniques such as crotnatogra lysis.

(YIS)

H — χ — S ³

σι-υ

Compounds of formula (V) may be prepared by reacting a compound of formula (W-a) wherein W- is a suitable leaving group, such as a halogen atom, with an intermediate of formula (IX). in an inert solvent such as 1-ethyl-T-pyrrolidine or

1,4-dioxane, an acid such as 1N hydrochloric acid in diettléíemel at 50 ° C to 250 bömérsékle- between ^these C

The compounds of formula <RTI ID = 0.0> (V) </RTI> can be subjected to a process of reaction whereby an intermediate of formula (X) is treated with i.p. or they are reacted fenkclonáüs szárroaxékívaí ye against reaktássokkal inert atmosphere such as oxygen-free argon or ni temperature gas in stmoszféráhun-20 C to 150 C, ^e.

Q (arc)

The general formula (X)! intermediates may be prepared by reacting a compound of formula (XI) or a reactive derivative thereof with a compound of formula (IX). Reaction B may be carried out under solvent-free conditions or in a suitable solvent, e.g. bis2 <2-times «in the reactor shock or in the reactor shock! as opposed to an inert atmosphere such as an oxygen-free argon gas or nitrogen gas, optionally in the presence of a base such as sodium bromide or potassium hydride 100 ^; 'C and 25 © -'C have announced! temperature.

♦ ♦ * κ *** ♦ * «

CH, * Ο; υο

ΤΑ

R ² *, Α% _Y Jk _; 3 t

Α. It is also possible to prepare a compound of formula XIII wherein W ² is a suitable leaving group, while V and Q are a compound of formula XIH given in formula 1-a with intermediates in a suitable solvent, for example in the presence of a base such as sodium chloride, in a reaction inert atmosphere, for example 1-oxygen-free argon gas or liquid gas, at a temperature between 20 ° C and 150 ° C.

_w .

o o § 11

05 'fos + · I v

ex © (XBt), 0¾

Y is a compound of general formula (IV) containing the correct chlorine or bromonaton! Compounds, i.e. simple compounds of formula IV-i, may be prepared by the introduction of a brine or chlorine atom into an intermediate of formula XIV, wherein W ² is as defined above, by treatment with N-bromosuccinimide or N-chlorosynchemaldehyde. by reaction in a reaction inert solvent against such Idoroformban széntetrakloridhas use C 20 ^and 125 C or at a temperature between ^these.

Conversion of compounds of formula (II), (IV) and (VIIi) wherein Q is a halogen atom (compounds of formula IIa into compounds of formula (I-a) wherein Q is -WHRv) is also analogous.

In the general formulas (1-a) obtainable by the methods described above, the compounds can be prepared as a mixture of stereoisomeric forms, more particularly a racemic mixture of enantiomers. which may then be separated by methods known in the art for resolution, such as the formula ác-z. Compounds can be converted to the corresponding dasteromeric salts by reaction with a suitable chiral acid. This can be followed by separation of the resulting saline salts by, for example, selective or fractionated crustalisation, and then the release of the enamomeric limes by the action of an alkali; An alternative method of separating the enantiomeric isomers of the compounds of formula (hair) is by flash chromatography using the chiral: stationary phase. The pure stereochemically isomeric forms referred to may also be prepared from the pure stereochemically isomeric forms of the corresponding starting materials, provided that

- 14 ** «χ * ν ♦« AA »« * * X «· * * ♦« A X ♦ * ** «» * ♦ going on. Preferably, if a specific stereoisomer is to be prepared, this compound will be synthesized by methods of silosphere preparation. Preferably, these methods are enauomeromerically pure starting materials! compounds.

It will be appreciated by those skilled in the art that the reactive groups of the diethyl ether products have to be protected with customer groups during the above-described processes.

Examples of suitable protecting groups which may be protected include the hydroxy, ampheo and caffoxyl groups. Suitable protecting groups for amino groups include, for example, κ-tert -oxycarbonyl or bessyloxycarboxylic acid. Suitable protecting groups for carboxyl groups include C 1-6 alkyl or benzyl, in the form of the appropriate esters.

The protection of the reactive groups and the deprotection can be carried out either before or after the operation.

The use of protecting groups is generally described in the following literature: "Protective Group» m Organic Chemistry ", published by Mcöntie, .1. Edited by W.F., Pennum Press, 1973; and "Protective Groaps in Organic Synthesis". edition, published by Greeae, T.W., and Wutz, F.G.M., edited by Wiley Innercteace. 1991.

The compounds of the general formulas (I) and (Ia) have antiretroviral properties, in particular, they are effective against the human immunodeficiency virus (English: HIV), which is the etlologic agent of the acquired Immune Syndrome (AIDS), HIV. Preferably, istm infects brown T-4 cells and destroys or alters their normal functions, in particular lunkefox expressed in the coordination of the immune system. As a result of this effect, an infected patient has a steady decrease in the number of T-4 cells, which are additionally worn abnormally. Thus, the immunological defense system is unable to fight infections and neoplasms, and thus, individuals infected with HIV infection usually die as a result of opportunistic infections such as pneumonia or cancer, and other pathological conditions associated with HIV-associated infections include , Kaposi's sarcoma, and central nervous system infection characterized by progressive muscle wasting, resulting in dementia and, for example, progressive articulation disorder, ataxia and loss of orientation. HIV infection caused by HIV may also be associated with peripheral neuropathy, advanced generalized lymph node disease (PSA), and the so-called AlDS-relational complex (PSA).

The compounds of the present invention, however, exhibit activity against HIV-1 strains that are already resistant to non-nucleoside reverse transcriptase inhibitors known in the art. However, the compounds of the invention are not. or they show only low affinity for glycoproteins of human ο - 1 acid.

In view of their antiretroviral properties, in particular antl-HIV properties, and more particularly their acylated HIV-f activity, the compounds of formula (I) or (fka), N-oxide, pharmaceutically acceptable addition salts, quaternary amine derivatives and stereochemically isomeric forms thereof medicine! for the preparation of preparations which. HIV vímssal. for the treatment of infected individuals. Alternatively, they can be used to prevent this type of infection. . In general, “the compounds of the invention may be used by physicians”. compositions for use in the treatment of warm-blooded viruses mediated by reverse transcriptase-mediated viruses or virus-dependent viruses. Pathological conditions that can be treated or prevented by the pharmaceutical compositions containing the compounds of the invention include, in particular, advanced conditions caused by HIV and other pathogenic retroviruses such as AIDS, ARC, EGE, and chronic central nervous system diseases caused by retroviruses, e.g. edema caused by the HIV virus and multiple sclerosis.

Therefore, the compounds of the invention, or any subgroup thereof, may be used in the preparation of a pharmaceutical composition for use in the treatment of said pathological conditions. Such pharmaceutical compositions are administered systemically to individuals infected with the HIV virus in an amount effective to treat the pathological conditions caused by the HIV virus and other pathogenic reteo viruses, in particular IÖV-1,

The compounds of the present invention, or any subgroup thereof, may be used in the preparation of a variety of pharmaceutical formulations which can be administered by a variety of methods well known in the art. Such a pharmaceutical composition may be any pharmaceutical composition used in the manufacture of medicaments for systemic administration. In order to prepare the pharmaceutical formulations of the present invention, an effective amount of a compound of the present invention, optionally in acid horseradish, is intimately admixed with other excipients . The nature of such carriers and / or other excipients will be to the detriment of the composition chosen for the route of administration. The pharmaceutical compositions of the present invention are conveniently formulated in unit dosage forms, in particular for use in oral, rectal, percutaneous or parenteral injection, such as in the preparation of pharmaceutical compositions for oral administration, in the form of pharmaceutically acceptable carriers and / or other excipients such as water, ghcolofca, oils and alcohols can be used to prepare orally administrable liquid preparations such as suspensions, syrups, meals, emulsions and solutions. On the other hand, solid carriers and / or other excipients may be used to prepare solid pharmaceutical compositions such as powders, pills, capsules and tablets, e.g. starches, sugars, kaolin, diluents, glides, binders, and disintegrating agents. For ease of administration, tablets and capsules represent the most advantageous oral unit dosage forms which are obviously solid and / or solid. . For the preparation of formulations for parenteral administration, the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example enhancers, may be employed. Injectable solutions may be prepared, for example, by using saline, glucose or a mixture of saline and glucose as carrier. Injectable suspensions may be formulated with suitable liquid carriers, for example, suspending agents. Also useful are solid form pharmaceutical preparations which are intended to be converted, shortly before use, to liquid form preparations. however, they do not have a significant adverse effect on the temperature. These additives precede »*« »φ φ φφ φφ **

X φ φ «φ

Φ. X φ φ Φ Φ φ φ φ φ} ί) .. * ♦ »» »g g g g gyárt g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g g. in the form of a plaster or ointment.

Suitable components for pharmaceutical formulations to encapsulate the inertness of the general formula (1-a), e.g. elecodextra may be added. Suitable title decoders for this purpose are:. δ- or γ-ethoxyxtria, or their ethers or mixed ethers, in which one or more of the hydroxyl groups of the cyclodexphene in the atrequirogens are substituted with C 1-6 alkyl, especially methyl. ethyl · or isopropyl: (e.g., randomly methylated S-cyclodexyrin); the moiety having from 5 to 6 carbon atoms in the moiety having hydroxyalkyl groups, especially hydroxyethyl, hydroxypropyl or hydroxycarbonyl; the alkoxy moiety has from 1 to 6 carbon atoms, with a carboxyalkyl group, in particular with a carboxymethyl or cadmixyl group; and alkylcarbonyl group containing 1 to 6 carbon atoms in the alkyl, in particular n-alkyl. Particularly useful as complexing agents and / or solubilizing agents are? -Cyclodextrin, randomly-released δ-cyclodextrin, 2,6-dimethyl-S-cidodextrin, z-hydroxy-b-cyclodextrin, 2-bidroxylyl-y-e-cyclodextrin; o -hydroxypropyproblylcyclodexynin and (2-carboxymethoxy) pro: p-13 -cycloxextrin. in particular 2-hydroxypropyl-3-dclodextril (abbreviated as 2-HP-8-CD),

The term "mixed ether" refers to a cyclodextrin moss chair wherein at least two mclodextrin hydroxy groups are etherified with different groups, such as mdboxipropyl and hydroxyethyl groups.

The average molar substitution for utilization of <.M-S ·} fcgntl as a mole of anlddroglucose is. average number of moles of alkoxy units. The average s2-dibasic horses (D.S.) refers to the average number of substituted hydroxy groups per aahydrogen moiety. The M.S. and D.S. values may be determined by various analytical methods, such as nuclear magnetic resonance spectroscopy (HMR), mass spectrometry (MSi, and infrared spectroscopy (IR)). 10, while the DS range is 0.125 to 3.

Other formulations suitable for oral or rectal administration are granules which can be prepared by melt extrusion of the formula (ϊ). and a suitable water-soluble polymer, and milling the resulting melt-extruded mixture. The grains you receive are then regular mud checks! They can be formulated into pharmaceutically acceptable dosage units such as tablets and capsules.

Such granules are solid dispersions containing a compound of formula (f-a) and one or more pharmaceutically acceptable water-soluble polymers. The preferred method for preparing such solid dispersions is the so-called self-potting extrusion method, which comprises the following steps:

a) mixing a compound of formula I-a with a suitable water-repellent polymer; b> to the mixture thus obtained: optionally »adding suitable mixing additives;

c) heating the mixture so obtained to obtain a homogeneous deposit;

d) pressing the ice thus obtained through one or more openings; and

e) cooling the melt until it solidifies.

The solid dispersion product is then ground or comminuted at 1500 µm, preferably 400 µm, more preferably; 25 ptn and most preferably less than 125 µm.

The water-retaining polymers in the granules are polymers having an apparent viscosity of -20 ° C; Dissolved in 2 volumes of aqueous solution - 1 mEa.s and 50.000 mPn.s, more preferred; 1 ntPa.s

Φ-Χ Φ Φ · · «« · Χ és és 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 700 also 700 mPa.s and 2 most eW> ov & ste «1 tsFa.s and WO tnPxs. For example, for example, for example, the present invention relates to the synthesis of alkali metal lye derivatives, bridges, hydroalkyl derivatives, catboxyl alkylcytosine derivatives. kafloxyalkyl cellulose numberTwo alkali metal salts, carboxyalkyl cellulose esters, starch esters, starch residues, pectins, choline slags, polysaccharides; polyacrylic acids and their salts, polymethacrylic acids and their salts and esters, methacrylate copolymer, polyvinyl alcohol, polytoluene oxides and ethylene oxide and propylene oxide copolymer. Preferred water-soluble polymers are the polymers sold by the German company Műn GmbH under the tradename Eudragit E, as well as hydroxypropylmethylcellulose translucents.

As described in WO 97/18839, one or more of the cyclohexane is used as a water-soluble polymer in the preparation of the above-mentioned granules. Such eicodexttinefc includes pharmaceutically acceptable, unsubstituted and safestituates well known in the art. cyclodextrins, in particular α, 3 or γ-cyclodextrins, or pharmaceutically acceptable derivatives thereof.

Examples of usable substituted cyclodextrins include the polyethers described in U.S. Pat. No. 3,459,731. Other substituted cyclodextrin derivatives include ethers wherein one or more of the cyclodextrin's htoroxy groups are hydrogen-C 1 -C 6 alkyl, alkyl having 1 to 8 carbon atoms in the alkyl moiety, or carboxyl having 1 to 8 carbon atoms in the alkyl moiety.

In particular, such substituted titanium oxide derivatives include ethers having from 1 to 3 carbon atoms in the hydrogen moiety of one or more hydroxy groups, the alkyl moiety having from 2 to 4 carbon atoms in the alkyl moiety. aryl or hydroxyalkyl groups, or carboxyalkyl groups containing 1 or 2 carbon atoms in the alkyl moiety, more particularly metal, ethyl, hydroxyethyl, hydroxypropyl. a carboxymethyl group or a carboxyethyl group. Particularly advantageous use may be made of Nógrádi, N., in Drttgs of the Futáré, Vol. 9, Vol. 8, pp. 577-578 <1984}. b-cyclodextrin ethers such as allyl-β-cyclodextrin, as well as the corresponding pether ethers, such as hydrex. Such an alkyl ether is defined as a methyl ether having a degree of substitution of about 0.125 to. Such a hydroxypropyl cyclodextrin can be prepared, for example, by reacting a S-cyclodextrin with propylene oxide, and the MS vasculature of such a compound may be from about 0.125 to 10, for example from about 0.3 to 3. Another type of substituted cyclodextrin is the sulfebatyl derivative.

The ratio of the chemical ingredients of formula (I-aj) to eicfodextrin can vary widely, for example in the ratio of 1: 100 to 180: 1. Preferably, the ratio of active ingredient to cyclodextrin is about 1:10 to 10: 1. the ratio of cyclodextrin to about 1: 5 to 5: 1.

It may also be desirable to utilize the compounds of Formula (I-a) in the form of nanoparticles which, when absorbed on their surface, contain a supersaturating agent in an amount sufficient to maintain the average serum size below. For this purpose, it is expedient to use surfactant modifiers which are physically attached to the surface of the compound of formula (I-a), but are not chemically bonded to this compound.

* ♦ 8 * 8 * ♦ * * 8 »« ♦ · X * «» * ♦ * <·

Conveniently useful formulating agents include known organic and inorganic excipients. Such excipients include various polymers, low molecular weight polygomers, products of natural origin, and lath fillers. Preferred mothers of uptake modifiers include: • nonionic and anionic surfactants

Another interesting application of the compounds of formula (I-a) is; when utilizing pharmaceutical mattresses in which the compounds of formula Ia are incorporated into hydrophilic polymers, the mixture is utilized as a coated film to form small beads, thereby providing a formulation which is readily prepared and suitable for oral administration. ..

Such beads have a central, rounded, or spherical core, a coating of a hydrophilic polymer and a compound of Formula I-a, and finally a coating layer of a polymer,

The materials that can be used as seed beads have a broad age range, provided that they are pharmaceutically acceptable and have the appropriate dimension and hardness. By way of example of such materials; such as polymers, inorganic materials, organic materials, and saccharides and derivatives thereof.

It is particularly advantageous to formulate the aforementioned pharmaceutical compositions in unit dosage forms which are easy to administer and provide uniformity of dosage for administration to the body. Dosage unit as used herein refers to physically discrete units which are capable of delivering the same amount of active ingredient to the body or containing a modified amount of active ingredient calculated to provide the desired therapeutic effect, when appropriate in combination with the required carrier and / or other excipient. Examples of such dosage unit forms are tablets (including coated or scored tablets), capsules, pills, powder packets, wafers, lozenges, injectable solutions or suspensions, and multiples thereof.

I do not find it difficult for one skilled in the art of treating infections caused by the HIV virus to determine the effective daily amount based on the experimental results described below. In fish, it is contemplated that an effective daily dose will be from 0.01 mg to 50 mg, more preferably from 0.1 mg to 10 mg per kg of body weight. It may be desirable to administer the desired dose in two, three, four or more subcutaneous doses throughout the day at appropriate time intervals. Said sub-dosage form may also be prepared as dosage units, for example, 1 to 101) 0 mg per unit dose. more particularly, from 5 to 200 mg of active ingredient.

The exact dosage and frequency of administration will depend, among other things, on the particular signal of the compound of formula (1) or (1-a) used, the particular disease being treated, the severity of the disease being treated, and the age, weight and physical condition as well as other medications used in a given tooth are well known to those skilled in the art. It will further be appreciated that said effective daily dose may be reduced or increased as a function of the effect on the subject and / or on the evaluation of the prescription medication containing the compound of the invention. The above-mentioned effective daily stalling practices should be considered as a guideline and are not intended to limit the scope of the invention in any way.

It is further contemplated to use in medicine combinations containing a known atttiretroviral compound and a compound of formula (I) or (fa). Thus, such pharmaceutical compositions of the present invention comprise a compound of formula (I) or (1-a) and another? 9 * 9 X * ♦ · *** «# * 9 * * X Λ <. ♦ * * ♦ ♦ * * "V" "" "" "" "" is a compound that causes andretrovtial effect or HIV infection in dsssta staph simultaneously, either intracellularly or sequentially. Emergency treatment too, Different active ingredients can be co-titrated by a single physician! In addition to the usual anttretroviral agents in the formulation, such well-known anttretroviral agents as mentioned in the examples are listed as such additional anttretroviral agents. nucleotide reverse transcriptase inhibitors by example! the following compounds; ztdovadlae (3'-azido-3'-deoxythymidine, AZT), didanosine (dldezasstnoztn; ddí), zalcdafine (didezoxicritdm, ddC), or lamivudime (d'-thia-z'-o'-dtdoxoxytidn); reverse: danscriptase inhibitors such as stsramme, pentamidine, ibymopentin, eastanospermio, dcxtran (destructinylfate), fescaraet-Halitaa (at trineralamylphosphonone), nevirapine (11-cycloprcprl-5,1-dl-dl-dl-dl-dl-dl-dl-d1-d). - dipyrid [te [3,2-b'2 ', 3' - ej [1,4] diazepis-on-one} and tacrine (tetrahydroaminoacridine); T1SO (teiralridro-indidazo [d] l -cycl, 4]: -bertzodiazepm-2 (III-yl) -one and tertiary compounds such as (S) -8-chloro-4,5,10,6-tetrahydro-Smethyl-o- (3-methyl-2-butyl) -nidazo [4,5,1-jk]: 1M, 4-benzo (liazpine-2 (lithionation; et-APA (trans) -aliafeacetacetamide) type compounds, such as α- [2-nitrophonyl] α-runoj-2.6-chlorobenzoacetate; ICU furniture such as RO-5-3335; mudesnodulant agents, such as levantol The compound of formula (I) or II-a may be combined with another compound of formula (I) or (I-a).

The following examples are intended to illustrate the invention.

For _x

ÁL.péida

To a atmosphere of argon gas® 0.00461 mole of 2: 4,6-trimethylphenyltin 5 toluene in M-dioxane was added 0.00439 mole of 5-bromo-2,4-d-chloropyridinidine prepared in 5 ml of 1,4-oxalane Hal. ,, then added to a reaction thus obtained Society ^íez 0.00548 mole of N ', N-bis (l-methyl! l) ethylamino DUO. The reaction mixture was refluxed with stirring for 20 hours, then the solvent was removed. The residue was dissolved in ethyl acetate, and the resulting solution was washed successively with a saturated aqueous solution of sodium nitrate hydrogencarbonate, water and a saturated aqueous sodium chloride solution, dried over sodium sulphate, filtered and the solvent was evaporated. The residue was subjected to silica gel column chromatography using a 1: 5, 1: 2 by volume mixture of nichloromethane and hexane, and finally 1: 1 by volume. Two pure fractions were obtained, from which the solvent was evaporated. thus, on the one hand, .3.35 g. (24%) of 5-bromo-4-chloro-N- (2,4-deactivated) -2-pyridin-2-pyridin-2-one: decolorization and 5-bromo-0.93 g (65%). -2-Chloro-N- (2,4-trimethyl-ethyl) -4-pyrimidinamine (Intermediate 2) is obtained.

AtLnélda

a) Melting with a mixture of 0.0156 moles of 4-hydroxy-5-chloro-2-n-methylpiperidine and 0, 078 moles of 4-hydroxybenzyl alcohol and stirring at 180-200 ° C for 6 hours. The reaction mixture was cooled and then triturated with boiling dichloromethane to give a 95% pure product which was dried. Then 1.2? g (33%) of 4 - [(5-chloro-4: -hydroxy-2-pyridinylidinyl) autHiO] benzamide (Intermediate 3) having a melting point greater than 301) AE is obtained (Intermediate 3).

b) Adding to Ö28 Moles Intermediate 3. 10 µl of Iphoroxide trichloride then. Equipped with an oil cooler containing the reaction mixture thus obtained. After heating at 80 ^V for 30 minutes, the reaction mixture was poured onto ice, and the precipitate was collected and washed with water (50 mL). After drying, the precipitate is further purified by column chromatography. The clean

The fractions were separated and the solvent was evaporated. There is thus obtained 4 - ((4,5-chloro-2-pyrimidinyl) aryl) -Ninobenzone (d) (interm. 4),

c) A mixture of 0.0132 mol of 4 intermediate in 75 ml of tetrahydrol brane and 1 ml of dichloromethane was stirred for 15 minutes, then. 0.0155 mol / l hydrochloric acid in diethyl ether is slowly added. After the addition was complete, stirring was carried out for 5 minutes and the solvent was removed under reduced pressure. This gives 3.98 g of 4 ': 1 (4,5-dichloro-2-pyridylmethyl) amine hydrochloride hydride (intermediate 5).

A3.. Example

a) Weigh into an argon gas amalgam metal reaction vessel, 0.01.34 mole of 2..45, t-trachloropyrimidine, 30 ml

1,4-dioxane, 0.0134 moles of 2.4, 6-tert-methylamine and 0.0136 moles of N, N-bis-methyl-ethyl) ethyl ether. The mixture was ^55> C temperature? Stir for 16 hours. The solvent is then evaporated and the. dissolve the residue in dichloromethane. The resulting solution was purified by flash chromatography on silica gel, eluting with dichloromethane and hexane 1: 4. then 1: 2 by volume. The fractions containing the product were separated and the solvent was evaporated. Thus, on the one hand, 0.15 g: 4, 5,6-trichloro-N- (2,4,6-trimethylphenyl) -2-pyrimidinyl (intermediate 6), and 3.15. 2.5 g of m.sub.2-michloro-N- (2,4,5-trimethylphenyl) -4-pyridinide (intermediate 7) are obtained.

b) Intermediate 21 7 0.004747 mol) ml .2,0 M is a mixture of 2-propanol · prepared aríirnóniutnliidroxid-oidatíal tariff reafcciöedényhcn be heated under pressure for 40 hours at 75-80 C. ^e., then the temperature was 110 to 115 ^{C is} raised to C. The solvent was evaporated to give 1.85 g of a residue. This 20 ml of 0.5 Μ, then 1.4 ~ AI: made ox.ánnal ammoniunfeídroxíd solution hörnérsékielet 125 ^o C? 18 hours. overheat. After evaporation of the solvent, 1.7 g of two isomers, namely 2,5-dichloro-N4- (2,4,6-trin-3-ethyl-fend) -4.6-pyrimidin-1-yl-dn (Intermediate 8) and , a mixture of? -alkyl-bi4- (2,4,? -trimethylphenyl) -2,4-pyrissidinediamine (Intermediate 9).

a) Argt gas atmosphere? while stirring, a mixture of 0.12 mol of 4 - ((1,4-dibidro-4-oxo-2-pyrididine) aminobenzomitrile and 90 ml of phosphorus oxychloride was refluxed for 20 minutes, and the reaction mixture was slowly poured into 75 ml of ice water. The precipitated solid is filtered off and suspended in 500 ml of water, the resulting suspension is adjusted to neutral pH with 20% aqueous hydrochloric acid, and the solid is again collected by filtration. After stirring in 2-propane and adding 1000 ml of diclone to the suspension, the resulting mixture is heated until all of the solid is dissolved, then the hood is cooled to room temperature, the aqueous phase is separated and the organic phase is separated off. the drying agent is filtered off to form a white precipitate in the hairs. The filtrate is then cooled. After cooling in a cupboard and filtration, 21.38 g (77.2%) of 4 - ((4-chloro-2-pyrimidinyl) aminobongronitrile {10. terherméfc).

b) In a sealable test tube, ö, © © 5 mol lo. Intermediate (0.006 mol) of l-bromo-2,5-pyrrolidite dichloride and 10 µl of trichloride were combined and heated at 100 ° C overnight. The reaction mixture was allowed to return to room temperature, then 2 g of glacial gel were added and the solvent was evaporated. The residue was purified by Oash column chromatography on silica gel, eluting with dichloromethane: hexane (9: 1 v / v). The pure fractions were separated and the solvent was evaporated. 1.31 g (84.5%) of 4 '- ((5-bromo-4-chloro-2-pyrimidinyl) 3-yl) -isobenzyl-3-yl (1 L hernia) are obtained.

χχχ * χ * «» »♦« φ «X ♦ ♦ X χ. · ♦ * * * ♦ X ♦

XV «» »» «Μ« «

AÁESÁk

Argon gas-attnosphoric reaction vessel x · 6,98564 was weighed after 4-amlsc-2.5, δ-carbonyl-itimidine, 0.1071 moles of 4-nobeaz »fM, 1? ml of I-methyl-2-pyrrolidone and 85.6 ml of 1M hydrochloric acid in diethyl ether. The reaction mixture was then placed in an oil bath at 130 ^° C and flushed with nitrite until the reaction mixture was stirred at room temperature. the ether «1 does not leave. A further 10 ml of 1-methyl-2-pyrrobolone was then added and the reaction mixture was heated at 145 ^° C for 16 hours under nitrogen gas. After adding 1,4-dioxane, the reaction mixture is refluxed, cooled and filtered. The filtrate was evaporated and the resulting residue was dissolved in dichloromethane. The resulting solution was washed with 1N aqueous sodium hydroxychloroethyl and then filtered. The solids were dissolved in 2-propanone and the resulting solution was applied to silica gel, eluting with 2% to 3% prop / vol. using hexane. The pure Ifactions were separated and the solvent was evaporated. yielding 1.63g (6.3%) of 4-t (4- & Nuno-5, _{6-dichloro-2-pyrimidinyl} jmninojfeetszoroirüt (Intermediate 12} are obtained.

& .VégteSEgk «k ^ Üiiá« í

EE..példa

a) In an argon gas dispersion 01) 0167 m 2 of diethyl ether to a reaction vessel containing the intermediate and then to a homogeneous solution thus obtained, 0.90169 moles of 1 M diethyl ether. of hydrochloric acid. The solvent was evaporated and 35 ml of 1,4-dioxoxane and 0.06322 mol of 4-aminobenzone A were added to the residue. The resulting reaction mixture was refluxed for 4 days under stirring. then evaporate the solvent. The residue was dissolved in dichloromethane, and the solution was washed with a saturated aqueous solution of sodium simpro-drogarcphenonate, dried, sprayed, and evaporated. This gave 0.79 g of an amber oil. This oil was purified by reverse phase high purity flash chromatography. The fractions containing the target compound were separated and the solvent was evaporated to yield residue I and residue 2.

The residue 1 was subjected to column chromatography on silica gel using dichloromethane containing 0% v / v to 2% v / v nreanol as eluent. The pure fractions were collected and the solvent was evaporated, yielding 0.0079 g (2.0%) of 4 - ((5-chloro-2 - [(2,4,6-yl: methylene)) amino): 4 -pyrimidinylamoylbenzylnyl (Compound 1) is obtained,

Residues 2 were subjected to silica gel column chromatography using dichloromethane containing 6 volumes of methanol to 2 volumes as eluent. The pure ions were separated and the solvent was evaporated. There was thus obtained 1.0044 g (1.0%) of 4 - ([5-bromo-2 - [(2,4,10-Srimethyl (ensl) amyl] -4- pyrimidin-1-yl) -nimino-benzonitrile (Compound 2).

b) Intermediate 2 (0.00285 moles) was added to the reaction vessel and diethyl ether was added, followed by addition of 0.00855 moles of 1 M hydrochloric acid in diethyl ether. The solvent was then evaporated and 2 µl of 1,4-dioxane was added. Subsequently, 9.90291 moles of N-aminobenzonitrile and 15 ml of 1,4-dfoxane are added to the reaction mixture, which is refluxed for 7 days with stirring. The solvent was evaporated and the residue was dissolved in dichloroethane. The resulting solution was washed with 1 M aqueous sodium hydroxide solution and the solvent was evaporated. The residue was wintered with 10 µl of dichloromethane, and the resulting precipitate was filtered off and dried, yielding 0.15 g. (13%) of o-11S-bromo-hi-o, N-phthro-trimethyl-methyl-hiO-2H-pyridinyl] -benzobenzone (compound 3) is obtained.

»« * «

B2 _; .péída

Intermediate 8, Intermediate 9 and Stoneware A3b. Prepared in a manner known in Example 1 (3: 1 w / w), 0.014422 moles of 4 to 8 mmol of triosophosphate are added and the resulting reaction mixture is heated in a pressurized reaction vessel at ISO for 5 hours. The material is then partitioned between dichloromethane and dilute aqueous sodium bicarbonate solution, followed by drying over sodium carbonate, filtration and evaporation. The reaction mixture was then stirred with steel and the precipitate was removed by filtration. The filtrate was further purified by reversed-phase high-performance liquid crystallization, the clear filtrates were separated and the solvent was evaporated, yielding 0.17 g of 4 - [(4-gmmo-5-chloroform - [(2.4, 6-Trimethoxy ^: fmyl} amino] -2-pyrimidine-triethyl triethyltrifluorate: EtOAc (1: 1 molar salt) (Compound 4).

M.péída

To a test tube: To a stirred slurry of intermediate gas gas SrA (0.063 mol) was added 0.0045 mol of 1 M, decolorized with 5 ml of 1.4 dioxane. hydrochloric acid solution, then stir the reaction mixture to evaporate the diethyl ether. After addition of 03709 moles of 2A-trimethylphenylimine, the tube was sealed and the reaction mixture was stirred at 156 T for 12 hours. The reaction mixture was then allowed to cool to room temperature and 2.2 g of silica gel and 50 ml of methanol were added. After evaporation of the solvent. the residue was purified by flash chromatography eluting with a gradient of dichloromethane, methanol and aqueous ammonium hydroxide to a volume of 99.5: 6.45: 0.05 to 99: 6.9: 6.1. The pure fractions were separated and the solvent was evaporated, and the residue A was dried to give 0.86 g (73.4%) of 4- [5-chloro-4 - ((2.4, h-trimethylphenyl) 3miao] -2 "ptnmjdmirjammo ), benzene nitrile (compound 5) was obtained.

M.nsktó

· A mixture of intermediate 5 (0.0025 moles) and 6.6075 moles of 2-tert-butylbutn-4-methylfemlamine in 5.0 ml of 1,3-dmxane was heated at 160 ° C with stirring for 1 h. and then concentrated to 2.0 g of xxlikage in a rotary evaporator. The material was then subjected to flash media purification using a 1: 1 by volume mixture of hexane and dichloroethane, pure dichloromethane, 1% methanol in 10% methanol in ddl-methane as eluent. This gives a product of 96% purity which is then recrystallized. At this time, 0.15 g (12.2%) of 95% pure 4 - [[5-chloro-4: -? -, 2-dibromo-4-methylphenyl) amine] -2-p-trimethyldiamine: Yield (compound 10).

Bfopéktó

To a slurry of argon gas in a test tube (6.007) was added 6.0075 moles of 60% (w / w) petroleum anhydrous sodium hydrate, and the resulting mixture was stirred for 1.5 minutes. and thereafter 0.0025 mol of 4 volumes of intermediate are added. The tube was sealed and the reaction mixture was heated at 150 ° C for 1.5 hours. The reaction mixture was then cooled to room temperature. 2.0 g of silica gel are added and the solvent is evaporated off. The residue was subjected to Essh column chromatography on silica gel, eluting with a gradient elution of dichloromethane: hexane 9: 1 to 100: 6, followed by oxymethane, methanol and aqueous ammonium hydroxide. 106: 6: 6 to · 97: 2.7 6.3). The pure fractions were separated and the solvent was evaporated. The residue was dried to give 6.73 g (86.2%) of 4- (j (5-chloro-4- (2,4,6-trimethyl) phenoxy) -2). -pyrinate «?! yielding benzomitrile (compound 6).

Abundant Example. (A) In a sealed test tube, 3 mL of 0.003 mole of t-fatty acid-5-dHaethylbenzate was treated with tertiary gas.

To the suspension in 1,4-oxalar is added 0.003 mole of a 60 wt% mineral oil of a trans-anhydride dispersion and 3 tus of 1-sulfonyl-2-pyrrolidine, followed by the addition of Ο, ΟΟ 1 mol / l of hydrogen gas. Subsequently, the test tube was sealed and the reaction mixture was ^{heated at} 100C for 1 hour. The reaction mixture was allowed to return to room temperature, then weighed into a stirrer and diluted with methanol (20 mL). Subsequently, 200 ml of water are added dropwise, and the aqueous mixture is then taken up in 300-300 ml of methylene chloride. and methanol (90:10 by volume) and extracted three times. The combined organic layers were filtered, dried and adsorbed onto 1 g of silica gel. The solvent was evaporated and the residue was subjected to sysfunctional dasb-oscillation chromatography purification by gradient elution with dichloromethane, methanol and aqueous asthmonium hydroxide in a ratio of 100: 0: 0 to 98: 1.8: 0.2. Fractions containing the target compound were separated and the solvent was evaporated. The marshmallow is triturated with hot acetonitrile, filtered and dried. There was thus obtained 0.20 g (47.6% of theory) of 4- [5-hro; rs-d- (4-caryl-2,6-disrethylphenoxy) -2-pyrimidinyl] amino] benzene (Compound 17). .

b) While stirring at 0 ° C, a solution of 0.010 mol of N-1-methyltyl) -2-propylanthine in 250 ml of tetrahydroforam is added with 0.010 mol of n-phenylyl lithium. the resulting reaction mixture is stirred cold for 30 minutes and then 0.15 mol of compound 17 is added. The resulting mixture was stirred under cooling for 15 min and then 0.015 mole of ethyl 2-br6-acetic acid was added. The reaction mixture was allowed to warm to room temperature and stirred for 16 hours. As a result, the reaction is completed by 50%. Then, 5 ml of water was added suddenly to the reaction mixture, and then, on a rotary evaporator, evaporated to silica gel. Next, purification by flash chromatography on Btotage Flash 40M was carried out with 0%, 0.5% and 1% by volume of mstanolic ammonium hydroxide solution, respectively. dichloro-tetrachloride, to give a white product which is a. a mixture of starting material and the desired product in a 1: 1 weight ratio. Then, as a final cleaning work, preparative high-performance liquid chromate blast cleaning. was carried out in test tubes containing 1 mmol sodium bicarbonate. After lyophilization, the lyophilized material was taken up in a total of 50 ml of a 1: 1 mixture of dichloromethane. The phases are separated, the aqueous phase is extracted twice with 25 ml each of dichloromethane, and the combined organic phases are dried over anhydrous sodium sulfate, filtered and dried in a rotary evaporator at 65 ° C under vacuum for 18 hours. Yield 0.33 g (13%) of the title compound as a white solid, m.p. 185-190 ° C (compound 50):

c) While rinsing with H 2 O, 0.00600 moles of a 60% w / w solution of mineral oil in sodium oil are added to 20 rt of tetrahydrofuran, and 0.00476 moles of Compound 17 are added and the resulting mixture is stirred for 5 minutes. Then, 0.00600 moles of 2,2-dimethylsulfoxyl chloroformate are added, followed by

The resulting reaction mixture was stirred at room temperature for 1 hour, then stirred under reflux for 4.5 hours and finally cooled. Thereafter, 20 ml of tetrahydroforan are added, followed by addition of 60% by weight of a 60% w / w dispersion of mineral oil in sodium oil. The reaction mixture was stirred for 24 hours and then the solvent was evaporated. The residue was dissolved in dichloromethane, and the resulting solution was washed with water and the solvent was evaporated, leaving A residue on silica gel. column chromatography, eluting with 1.00: 0, 99.5 and 0.5 v / v methanol / triturate. The fractions containing the eluent were collected and the solvent was evaporated. The residue is purified on a Gtlson apparatus, crystallized from srtajd 2-proparolol, the precipitated crystals are filtered off and dried. Yield: 9.60 g (23%) of the following compound (Compound 60) as a white solid:

dl 0.0020 mol Compound 17 40 ml. To the slurry of tetrahydroforate is added in one portion 0.24 g of tartaric anhydride and the gas-evolving mixture is stirred for two hours to give a bright yellow suspension. At the same time, a solution of 0.020 moles of 2,2'-oxybisacetyl fondue in 10 ml of tetrahydrofuran was cooled in an ice bath, and the cold 2,2'-oxybisacetylldond solution was added via cannula dropwise over a period of 10 minutes to the above suspension. After addition, the mixture is brought to room temperature and then. stir for three days. An additional 0.24 g of sodium hydroxide was added and the reaction mixture was kept in an ice bath for two days. After: 30 minutes. the course. A mixture of 0.150 moles of metartol and 0.150 moles Tris-Hantin was added dropwise. the reaction mixture was heated to room temperature and after 16 hours poured into diethyl ether. The resulting diethyl ether mixture was extracted with a saturated aqueous sodium hydroxide solution, and the aqueous fraction was reextracted twice with diethyl ether. The combined ethereal extracts were backwashed three times with water, and dried over magnesium sulfate. 2.91 g of an oily residue are obtained, which is subjected to reverse phase preparative high-resolution liquid flash scrubbing. By lyophilization of the fractions containing the target compound, 0.17 g (14.5% yield after purification) of the compound of formula (61) are obtained as a powder. compound);

«*« «XX

A pressurized reaction vessel was charged with argon gas (0.00286, 12, intermediate, 0.00571 moles, 4-aliquots), 0.00140 moles of 1 M hydrochloric acid and 8 ml.

1.4-dioxane. The reaction mixture thus obtained is then heated under a stream of anhydrous gas in an oil bath until the total amount of solvent is evaporated. At this time, 3 ml of 1-iuethyl-N-pinolidirtone was added and the reaction mixture was heated at 220-240 ° C for 3 hours. Then heat to 210-220 ^: C! six hours. continue, u-dissolve the residue in 1,4-diosanbar. The resulting solution was evaporated and the residue partitioned between dichloromethane and 1 N aqueous sodium hydroxide solution. The organic phase is then filtered, dried over potassium carbonate and evaporated. The resulting product is then subjected to preparative reverse-phase chromatography, and the pure fractions are separated and the solvent is evaporated. Thus, 0.01.65 g (1.1% after lyophilization) of 4 - {[4-anmm-5-yloxy - [(4-chano-2, 3'-dimethylphenyl) -am] (2-pyrimidinyl) a] Yield: nrinobenzonitrile trifluoroethylene (1: 1 molar salt) (Compound 19).

Bfopélda

While stirring, 0.0011 mol of intermediate 11, 0.0014 mol of 2-dimethyl- (2-propyl) phenylamine, 0.0022 mol of N, N, N '', N ^? -! e! rameiil-l, S-Disadvantages: and 2.3 ml of 1 M hydrochloric acid solution (from Ö023) in 25 ml

The mixture of 1.4-dto: xane was heated at 95 ^° C for 16 hours, then the solvent was removed by rotary evaporation and the residue was subjected to reverse phase preparative HPLC. Líofihzáljuk frakojókat containing the desired compound, yield 0.23 g (48%) of ^{198-201; compound} was obtained (40), mp C képiéin following:

Bfogélda

0.00219 moles of 4-α-pyrine-2,5-dimethyl-3,4-isomer and 0.00218 moles of 4 - [(5-bromo-4-, 6-d-toluene) -2-pyrimidinyl] arainoylbenzoyl. to the mixture is added 0.0024 moles of N, N-di (methylethyl) ethylamine, and the reaction vessel containing the mixture is then sealed and then heated under stirring at 155-160 ° C for 1.5 days. The reaction mixture was then cooled to room temperature and subjected to silica gel column chromatography on silica gel using toluene / methanol as eluent. Purification was completed by preparative high folyadékromatógralással when (5%) of 0.05 g of ⁿ olvadásponttá 259-260 C. 4 - ([5-bróffi któr'6-4 - [(4-2,6-eiaíto -dimethylphenyl: m.p.bisoj-2-pyrimidinyl; m.p.

BHLkÓkla

To a solution of 0.00218 moles of 4 - [((5-bromo-4, 4-dichloro) -2-pinmidisilumino] benzonitrile in 10 ml of 1,4-dioxar is added successively 0.0022 moles of 2,4,6-trimethylmemlamm, then N, N-di (methylethyl) ethylamine (0.0024 mol), the reaction mixture containing the reaction mixture was sealed and the suspension was heated in an oil bath (12: 0-130 ° C) for 91 hours with stirring. Subsequently, the reaction mixture was cooled to room temperature and an additional 15 ml of N.N-d (methylmethyl) ethylamine was added. Subsequently, at 120-130 ° C for 64 hours. then at 150 ° C for six hours. The reaction mixture was then at room temperature ***

♦ ♦ A A * ♦ X. ♦ * AA x A * * *

The mixture was refluxed to -26 ° C * *******, quenched with 5% aqueous sodium hydroxide solution and extracted with cold 1M aqueous phase, the aqueous phase was backwashed with efyl acetate and the combined organic phases were stripped and evaporated. The residue was purified by flash chromatography on silica gel using dichloromethane as eluent. The obtained pork chaff was further purified by preparative high-resolution liquid grater screening when 4- (5-bromo-4-chloro-6 ~ [(2,4,6]) melting point at 220-22 ° C was used. trimethyl & nyl) -axia-2-pyrrolidinyl] asphalt (Compound 41).

SLU & ito

0.0043 mole of 4-ateninohenzonhril and 0.0021 mole of the compound of formula

A mixture of nd 1,4-dioxane was stirred at 100 ° C for 16 hours and then. solvent is removed in a rotary evaporator. The resulting solid was triturated, -then the residue was dried at 40 C ⁿ 16 hours under vacuum. 0.432 g (55%) of the title compound, m.p.> 300 [deg.] C., is obtained (Compound 43):

Weigh 0.0056 to a pressurized reaction vessel. moles of the formula:

O, O l 163 4 oTol-aminobertzmnlrí.lf and 2 (1-a-nd 1 -melii pirrolidiöönt the mixture was heated at 140 ° C Shoot hours and then cooled to room temperature, and then acetonitrile _cs. Which water was added. The resulting precipitate was filtered off and recrystallized from acetone-yttrium to give 1.27 g (52%) of a m.p. ⁼ 2660262 ^° C. 4-i: 5-bromo-4- (4-chlorophen-2-ylmethylphenosi) -6-methyl. -2-pyrimidine; m.p. = 150 ml. BenzoBIN (Compound 44) is obtained.

While stirring, would 0.001 mol of IL and a mixture of 0.00473 of 2, 6-dimethyl-4-ethninobenzene® be stirred at 150 ° C? After stirring for 16 hours, it is added in methanol. The solution thus obtained is evaporated onto 1 g of silica gel and subsequently eluted with a mixture of hexane and dichloromethane (1: 1 by volume) in hexane and dichloromethane. 1: 4 (v / v) and finally only dichloromethane, using 2 to 2 l of solvent each time. The fractions containing the desired compound were sued and the residue was vacuum dried at 45 ° C. Dry for 16 oats. The product thus obtained is filled into a 4 ml vial with dichloromethane and the solvent is evaporated. give 0.120 g (28.6%) of melting 277-2SÖ ®C 4 - ([5-O- Bronson «4 ciaíB> 2, um-dimeííi'fenS) atn.inoj ^-2-petty {H The resulting dichloromethane (> 45 · .. compound) is obtained,

Example B4

It can be pressurized in a reaction vessel from 0.00250 moles of 4 - ([5-bromo-4- (4-cyano) ro-2,6-disnsidine-6-chloro-2-pyrimidinyl] -jamisobenzone and 0.015 moles of 0.5 M, The mixture was stirred at 150 DEG C. for 4 days and then allowed to stand at ambient temperature for 2 days. Water was added slowly until no precipitate formed and the mixture was stirred for 2 hours. The filtered material was recrystallized from acetonitrile to give a fraction of 0.5Sg, fraction 1 was evaporated to give fraction 2. The fractions were combined and purified by column chromatography on acetonitrile to give a residue. , when 0.44 g (40.5%) of 4 - [(4-amino-5'-bromo-6- (4-cyano-2 _; 6-methylphenoxy) -2-pyrimidinyl] amino } bfisn2.m »tnit, of which one sample at 86 X was 0.2 m mHg pressure® for 16 hours, to give compound 46: ®.

BX.péjrb

To the pressurized reaction vessel was added 0.000660 moles of 4-j5-bromo-4- (4-cyano-2,6-dimethylphenose) -α-chloro-2-pyrrolidinyl} -ninoylbenzonitrile, 1 mL of tetrahydrofuran and 0.00198 mol. 1-Pyrrophiasmethylansin and the resulting reaction mixture were heated at 75 for 16 hours. After addition of methyl chloromethane, the reaction mixture was washed with water, dried, filtered and the filtrate was evaporated. The residue was purified by flash column chromatography eluting with methanol: methylene chloride (1: 9, v / v). mixture. This gives a solid which is triturated with acetonitrile. To the resulting solution was added 0.4 mL of 1.0 M hydrochloric acid in diethyl ether and the resulting mixture was stirred in an ice bath. Cool. After filtration, 0.19 g (50%, 6%) of 4 - ((5-bromo-4- (4-octaat) -2,6-dimethylphenoxy) -6- (1 H ), ethylamino-O-pyrimidinyl-amino-iminonitrile-hydrocarbonyl salt (Compound 47).

Blfrjfrjdií

It can be placed under pressure in a reaction vessel. 0.00064 moles of 44 (5-chromin-4- (4-cyano-2, 6'-dimethyl-tetrachloro-Z-pyrimidinyl) -thiobenzene-1-yl), 3 ml of spherahydroforan, 0.06 g of O-methylhydroxhammt, tetralurofuran and 00067 moles of 1N aqueous sodium hydroxide solution and the resulting reaction mixture was stirred at room temperature for three days, at 75 ° C for one day, at 90 ° C for one day and finally at 11 ° C for two days. To 60 g of O-Mephylhydroxyam are added 4 ml of a solution of thyracrylhydroferaph and 0.00719 mole of 50% aqueous potassium hydroscrd, and the resulting mixture is poured into a reaction vessel and the reaction mixture is heated at 11: 0 X for three days. The solvent was evaporated and the residue was dissolved in dichloromethane. The resulting solution was washed with a saturated aqueous sodium dihydrogencarbonate solution, then with water, filtered over anhydrous sodium sulfate, filtered and filtered. The solvent was evaporated and the residue was purified by column chromatography using a mixture of dichloromethane and methanol (v / v) as the fractions containing the pure product were separated and evaporated. Thus, 0.15 g (51%) of the title compound, m.p. 185-1 salt ^C -4-U5-bromo-4- (4-clano-2,6-methylphenyl) -o- (is) ethoxamethyl} -2-pyrimidinylamine, isobutylated. This was then stirred at 0.2 mm pressure and 8 ° C for 16 hours to give compound 48,

a) At 0, with stirring, 0.70 ml (10.005 moles) of 1- (cetethyl) -2-propyl alcohol and 200 ml of tetrahydroferan are added with 2.0 plates (0. 5 moles) of u-budifrtium and 30 minutes at the same temperature. stirring in titanium 0.005 mol of compound 17. The resulting reaction mixture was stirred under stirring for 30 minutes and then treated with 1.5 ml (10 mmol) of bis-acetic acid-dimethyl ester. The reaction mixture was then left at room temperature and stirred for three hours. In a separate reaction mixture, while stirring at 0 ° C, is added 2.0 ml (5 ml) of n-butylpholyl in a solution of 0.70 µl (5 mmol) of N- (methylethyl) -2-propylminine in 50 µl of trihydroxyburon and the resulting reaction mixture is stirred for 30 min. allow one minute to react. Thereafter, this reaction mixture is stirred at. This procedure was repeated once more and 0.5 mL of skeleton was added to the reaction mixture at the same time. The reaction mixture was then concentrated in a rotary evaporator on silica gel and purified by flash chromatography using 0% v / v, 10% v / v and hexane containing 20% ethyl acetate as the eluent. mp = 195 197 ^C. Thus, the C, the desired compound of formula (Compound 56) as a white solid ;:

b) To a suspension of Compound 17 in 40 ml of NN-dintethyl tetrachloride was added 0.24 g of sodium hydrate and the resulting gas evolution mixture was stirred for 90 minutes. A solution of i-t-dichloro-1,4-butanediol in 10 ml of N, N-dbnettoleate was prepared and cooled in an ice bath. The reaction mixture from Compound 17 was then added to a cold solution of I-mediotyl-1-propyllamine, and the combined mixture was stirred at room temperature for 42 hours. Then more. Sodium monohydride (0.24 g) was added and the reaction mixture was stirred for three days, diluted with diethyl ether and poured onto ice. The precipitate was collected by filtration. A. The biphasic filtrate was separated and the acid-aqueous fraction was added twice more to diethyl ether. extracted. The combined diethyl ether fractions were washed with distilled water with a small amount of manure, dried and the solvent was evaporated. The residue was subjected to silica gel column chromatography, followed by reverse-phase preparative high-performance liquid chromatography and the end of the appropriate fractions immediately; lyophilization after cooling to give 0.1 g to 7 g; (7.8%), m.p. 252-233 ^° C (compound 57).

* Φ * χ # ♦. 29 -

c) 60% by weight of a mineral oil hydride dispersion in mineral oil and tetrabidxophorane were weighed into a diethyl alcohol under argon atmosphere, and the resulting mixture was stirred at room temperature for 1 minute and then compound 17 was added. After stirring for one hour, chloroformate ethyl acetate was added and the reaction mixture was stirred at room temperature for a further 1 hour. stir and evaporate the solvent. The residue was partially dissolved in dimethyl sulfoxide and the resulting solution was filtered. The filtrate is purified by reversed phase crosstrain and lyophilized. 0.47 g (Ig%) of the following compound (58) is obtained:

d) A solution of,, Ö47 moles of 4- {f5-an5-100-<4-elano-2,6-dimethylphenoxy 2 2-pyrimidinylimolymerized] in 10 ml of a mixture of acetic anhydride and 1 ml of 2-propane was stirred at room temperature. stirred for hour, then fohnelegirjük 55 C and ^this temperature a further 3 ml. acetic acid is added. The reaction mixture was heated for an additional 18 hours and then stirred at room temperature for b days. The reaction mixture was evaporated in a rotary evaporator, and the resulting solid was subjected to column chromatography, eluting with 0% by volume methanol containing 0.5% by volume, 1% by volume, 1.5% by volume, and 2% by volume methanolic methanol. using. The melting point of 290-295 ° C gives the following compound (XXV) which is then dried under vacuum at 60 ° C for 1 hour to give compound 49:

jordan

0.0005 after mixing 4 - :( 4- (4-cyano-2, O-dimethyldenoxyl-5- 3-titro-2-pyrimidin-2-yl) aminobenzenesulfonate, 0.100 g of a 10 wt% palladium-on-carbon catalyst and 20 ml of dimethylmorphane overnight. After the addition of 0.0015 moles of hydrogel gels (3 molar equivalents), the catalyst is filtered off and the vacuum rotary evaporator is dried and vacuum dried at 40 ° C for 1 hour to give 1515 g (84%). Melting point> 4 ° C gives 4- (5-amino-4- (4-cyano-2, 4-dicyclo-ethyl) -2-butyl-dihydro-ninolin-4-benzoate (Compound 50).

^ BLS Geld

0.001 moles of 4 - [(4- (2-methylthiophenyl) -ta-5-nitro-2-pyrimidinyl] -iamizole] and 0.025 g of a 10 wt. After stirring for 1 hour, the solvent was evaporated under rotary evaporation and the residue was taken up in 20 ml of tetrahydrofuran and 1 ml of acetanol, followed by addition of additional 0.5 g of hydrazuo and the reaction mixture was stirred at room temperature for 1 hour. an additional 0.5 snl of indrazine was added and the reaction mixture was stirred for an additional 1 hour at room temperature. The reaction mixture was then purified by rotary evaporation of 1 g of silica gel in a rotary evaporator, followed by 0.5 volumes of 10 , a phosphorus containing methanolic ammonium hydroxide solution The fractions containing the desired product were subjected to preparative high performance liquid chromatography to give 0.24 g (70%) of m.p. 224-225 mp 4 - [. 6-Irmethyldiaml} 8mmo) -2-phthymidineJarmn.ojbenzottiiri.lt (51. compound).

B2fkjfélág

A sealed reaction vessel was charged with 0.001 mole of Compound 3, 0.0012 mole of phymethylmercarbohydrate, 0.020 g of PdíPPh ^ ACIg, 0.010 g of copper (I) solution, 3 ml of aqueous TFA solution and heated at 110 ° C for 10 hours. . A second portion of this was followed by the addition of 0.020 g of Pdt'PPb.sub.2 catalyst, 0.010 g of copper (i) iodide and 3 ml of aqueous triSnoroacetic acid, and the reaction mixture was stirred at 110 ° C for 10 hours. This is followed by concentration in a rotary vacuum separator and purification of the remainder of the residue by preparative high-resolution liquid roto-gravity. Fractions containing the desired product are encapsulated. and subjected to reverse phase preparative HPLC purification. Finally, the stream of oltrogen gas was dried under vacuum at 40 ° C for 1 hour. 0.01 g of m.p. 165-175 [deg.] C. is obtained: 4o: {5-Elinyl-4 -: [(2,4, 5'-pyridinyl] -phenyl) -amino] -2-phenyl-phenyl} -armininol-benzoththalm (compound 152).

0.000906 moles of Compound 3, 0.000006 moles of phenylphenylstannate, 0.0027IS moles of Et2O3 and 3 ml of 1,4-dloxate were charged into a nirtogen gas-sealed resin and heated at 110 [deg.] C. for 1 hour. The reaction mixture was cooled and evaporated in a rotary evaporator. The residue was subjected to reverse phase high performance liquid chromatography. and then dried under a stream of argon. After further drying in vacuo, 0.0845 g of m.p.-4- [5, 5-phenyl-4 - [(2,4-h] trimethyl-fodyl) - [8, 9] - [2-pyridinyl] -dilyl] is obtained at 209-214 [deg.] C. The residue was purified by flash chromatography to give benzoylmitryl (Compound 53).

Under a argon purge-sealed reaction vessel, 0.001 mole of Compound 5, 0.22 ml of thetaethyl acetate, 2 ml of 1,4-oxoxane and 0.112 g of P1PhPh1a1a are weighed and the resulting mixture is stirred at reflux temperature for 1 hour. heated. Additional tertiary carbonate and PdfPPh3 are then added and the reaction mixture is heated under argon gas with stirring. Finally, the reaction mixture was rotated under vacuum * Φ * X ** * Φ

- 5 · X Φ Φ * Φ * · Φ X * ** φ φ * φ

The concrete was opened in a beaker and then subjected to a preparative high-resolution Etlyadefferromiographic screening. It was then dried in a trace gas stream and then under vacuum at 60 ° C for four times at a rate of 0.422 g. Melting point: 4 -: [(5-ethyle-4-yl (2,4,6-: r: 3-methylphenyl) -amyl] -2-piperidinyl] -amino] -benzonithyl (Compound $ 4).

0.001225 moles of Compound 3, 0.001470 moles of copper (0cidium iodide and 2 rmL of Ν, Ν-dimethyl transfer agent) were charged to the sealed reaction tube and the resulting reaction mixture was heated under stirring at 100C for 1 hour. The residue was purified by column chromatography using a 1: 1 by volume mixture of dichloromethane and hexane followed by dichloromethane as the eluent. dried to give δ, Ő8Ő4 g (24%) · mp 254-259 (compound 55):

Tables 1, 2, 3 and 4 are as follows. The compounds of formula (I-aj) list compounds that were prepared in an analogous manner to the methods described in the examples previously described.

Table 1 as fi

-éh.

íti Ί; '

The compound is a salt. In the example no. Y Physical data f. 8am cl - ·> X-. 8am Br mp: 227-228 A; 22nd 813 .. WOMAN? mp: 224-226 ^a C

Table 2

R ^: H

♦ X ♦ »

Dry. s. Eg. s. R ^a R ^e X v Q o.p./só Third Bib. ch ₃ CH at. NH Br H 227-228 4th 82 CH ₃ ch ₃ at. NH cl nh ₂ 241-242 'C; trifluoroacetate salt (1: 1> 5th 83. i ch ₃ cb ₃ ch ₃ NH cl H 224-226 6th 85th CH ch ₃ ch ₃ 0 the H 218-219 7th 85th ch. cn. ch. s the H 264-266. 8th 85th Oh; Br ch ₃ She the H 237-238 9 83rd CH 8r ali ₃ NH cl H 217-219 10th 84th Br CH ₃ 8f NH cl H 262-263 11th 84th Br Br F NH the H 200-202 'C 12th 84th CH _λ € (CH ₃ > ₃ CH NH the H 214-215 13th 84th <B 3 CN CB-- NH cl H 283-283 14th 84th k. i cl CB, NH cl H 243-245 ° C 15th 85th c 8r ch ₃ SHE the H 244-247 16th 85th IC cl ch ₃ SHE ci I-i 232-235 17th Plenty. ch. CN cb ₃ O Br H 288-289 18th 85th cn. CN ah 0 cl H 283-284 19th 87th O-H CN ali ₃ NH cl NH, 266-268 'C; Irifh! C ·! ·; · ·: Χ · '; 8 ·; ·.> (1: 1) 20th 83rd Cl. cl ah NH 8r H 253-254 'C 21st 83 CH? Br ah NH Br H 243-245 25th 823rd C8 ₃ CN CB :. NH CN H 275-290: 'C; trifluoroacetate salt (1: 1) 24th 823rd CH Br ch. NH CN H 291-299 25th 814th CH ₃ CN ch. SHE Br nh-ch ₃ 248-250 ° C 26th 814, Cl h CN ch. 0 Br NH, 2S5-256 'C 27th 814th CH CH c. She Br NH, ' 28 814th cr ₃ CH ah 0 Br NH CIH 213-214'C 22nd 814th ch. CN ch ₃ 0 Br Nl-LCNC 263-264 30th 814th ch. CN ch ₃ 0 cl NH, 272-774 'C 31st 814th CH ch ₃ ch ₃ She the .NH, X. 199-202 'C 32nd 811th cn ₃ ch. ch ₃ NH woman. H > 300'C 33rd 85th ch ₃ ch ₃ ah _: SHE 8r H 207-215'C 34th 85th CH ch ₃ ah 0 cl cl 225-226 'C 35 85th CH CN CH SHE cl cl 273-276 36th 86th ch, CN CB, SHE cl Br 283-282 37th 85th CH ch ₃ ch ₃ . She cl Br 214-215 40th 88th CB, : CH ₁ CH ₃ ), ah NH Br H 198'C; writes of Bioracia (H21

♦ XX ♦ ♦ ΧΧΧ XXXX XX ♦ ♦ X Α X

X X X XXX

X X X * Κ

Dry. s. Eg. s. R ^a R ^b R ^c X Y Q O / pJvjö 41st S; 0th ch _3: CH; % C NH Sr cl 220: 'C 42nd 89th ch _3: CN cs. NH Br cl 259 ^: C 43rd Ski 1. CH CN CH SHE NON c. H > 300 ^: 'C 44th ΒΪ2. CH CN · ch, SHE Br ch ₃ 260 ^: 'C 45th B13. CH CN CIH NH Br H 277x: 46th S14. ch ₃ CN ch ₃ SHE FIR nh ₂ 255 'C 47th 815th Cll ₃ CN ch ₃ 0 FIR 208 'C; HCl (I: I! 48th B16. CB, CN ch. SHE Br -NK-Ox h. 185-186'C 49th S17d. ch. CN ch. SHE Nicotinic i-COC, H 209-295 50th B18. CH; CN CH SHE NH? H > 300 'C 51st Ski 8. CH _? CIN. CH NH -nice • volts. H 224-225 'C: 41: 1) 52nd S20. ch ₃ CIN, CH? NH CN H 165-175 ° C 53rd B21. CH CK ₃ · CH, NH comb H 209-214'C 54th S22. CH CS ₃ CB, NH -CH-QC H 237-242 'C: trl' flora oil (13) 5.5. .823. CH ch ₃ CB, NH ~ ch === ch ₂ H 254-259 'C

Table 3

The chemical. Ref. For example, s. Z Physical data (p.p) 38th BÍ7 <:. 194-196'C 56th & 8Í7. -CH _r COOC (CH,),. 195-197 57th B17b. CHO 232-233 58th SÍ7e, -COOCdU 209-210-'C 59th B6b, -0) 2-0300¾ 185-190 'C 60th B6E. -Oíi-COOC (CH,) ^ 168-169 61st Siid. -CO-O-ON> -CO-OOH 184-185

Table 4

** ***

Vgy. s. Pld.sz. sa rb X Y Q Physical data (p.p) 39th B5. cl cl s Br H 198-200 ^° C

C. Pharmacological Example

CLpélda

A rapid, sensitive, and antotabulated experimental method is used for the in vitro evaluation of murine HIV agents. The experimental cell belts used are T4-cellwnab (MT-4) scrambled with HiV-1 virus, which is described by Koyanagi et al. Cancer, 36, 445-451 (1985), discloses series of highly sensitive HIV infections. The end point is the resolution of the citnpatient effect induced by HVV. All HIV infected cells as control cells. viability is assayed by spectrophotometry by in situ reduction of 3- (4,5-dithiolyl) -dazol-2-yl) -2,5-diphenylmethylene-5-one (MTT). The 50% cytotoxic concentration (expressed as tX'50 μΜ) is dinylated as a 50% reduction in the concentration of the test compound in HIV infected cells by a 50% reduction in the concentration of the test compound in the following formula. Who:

(OD r) | _HV - (ODAH

-—--—-------- ^ expressed in chips,

YOU _C ) _{k <} niri!} g - µ (® <;) h: y where (OD-β) → {v is the optical density of the test compound at a given tongue concentration in HiV-infected cells; (OE? Tfepy control is the optical density in untreated HiV-infected cells; (δc) for coarinic untreated uninfected conidocytes; mens. Optical density; each optic density is determined at 540 am.). detiniáljnk rstfet required dose strength of the defense gáöási konceottációt 50% (IC5Q nM units) .. ÍC5Q. the ratio of CC ₅ ttz than q and the selectivity of the covering (SI) is defined. the compound (I) compounds effectively inhibit HIV-I virus Specific ICsp, CCgo and Si values are given in Table 5, Table III.

Vgy.sz. ICjq tuM) % >> 10 ^! Ski 2 .. 0,030 82.6 2230 Third 0006 4.4 738- I 0,004 10.9 2287 4th 0002 10.0 5555 5th 0,002 0.4 178: 6th 0:09 > 100 11049 7th 0,084 > 100 > 1182 8 0012 > 100 > 8298 9th 0003 1.2 376 0,002 > 200 > 71 428 -isosorbide. 0,002 > 100 > 52 631

Vgy. s. ICip t .ti.S'l) C-Cjt) (μΜ) SKI 10th 0, (8) 5 0.4 92 11th 0,002 0.4 183 12th 0.20 48.5 2393 13th 0.0005 0.4 860 14th 0,002 0.4 181 15th 0,010 > 100 > 96ől 16th 0,010 > 100 > 10416 17 0,002 > 10 > -645 µ 13th 0.001. > 10 > 7142 60th 0,002 74.52 39 223

* »* ♦ ** ♦«

Claims (19)

Patent claims: 1. A compound of formula (I-a) - in the formula: q is 0, 1,2,5 or 4: R ¹ is hydrogen; arilcsopon; fenuilesoport; alkyl group containing 1 to 6 carbon atoms of the shikyl moiety; C 1-6 alkyl; an alphaoxycarbonyl group containing from 1 to 6 carbon atoms in the alkyl moiety; ibrmyl, alkoxycarbonyl containing 1 to 6 carbon atoms in the alkyl moiety, alkoxycarbonyl having 1 to 6 carbon atoms in the alkyl radical, or. alkyl having from 1 to 6 carbon atoms in the alkyl moiety and having from 1 to 6 carbon atoms bonded to alkylcarboxyloxy; or alkoxyalkyl-carboxyl substituted by 1 to 6 carbon atoms in the alkyl moiety substituted with 1 to 6 carbon atoms in the alkyl moiety; R ^2s is a cyano group, a mninocatbomloseport, a mono- or dimethylaminocarbonyl group, or an alkyl group containing a tertiary carbon atom substituted with a cyano, atninocarbonyl or mono- or methylmethylaminocafonyl group containing from 2 to 6 carbon atoms substituted with a cyano group. or an alkyl group containing from 2 to 6 carbon atoms substituted with alkoxy; each R ^{2 is} independently a fc gene; bidroxiicsoportot; cyano or -C <- “Ö) R ⁶ - general formula. unsubstituted alkyl having from 1 to 6 carbon atoms; A cycloalkyl group containing from 3 to 7 carbon atoms; optionally alkenyl groups containing 2 to 6 carbon atoms optionally substituted with one or more halogen atoms or cyano groups: with one or more halogen atoms. or a C2-6 optionally substituted C2-6 alkyl group; An alkoxy group containing from 1 to 6 carbon atoms; alkoxy carbonyl containing 1 to 6 carbon atoms; karhoxilesoportoi ;. esanoesoportot; HÍtrocsopörtot; amino; mono- or di-6 carbon atoms; polifealogénmetílcsoportot; polibalogénmetoxícsoportot; pobhalogénmetílttoesoportöt ;. or -S (-O), R ⁶ ; -NH-S (-O) pK ⁶ ; -Q = »δ) R ⁶ ; -NÜCp-one; -C { «O) NHNH 2; -N.BC (O> R ^e ; -CteNH) R ⁶ ; or (e) represents (C); and, in the latter formula, A is completely adsorbed to each other. or a methyl group or a CR ⁶ group and an Imio 8 group or an oxygen or sulfur atom or a -NR ⁶ group; p is 1 or 2; and R ⁰ is methyl, amino, mono or methylmethyl or polyhaloethyl; -361 "represents alkyl having 2 to 10 carbon atoms, deactivated with 2 to 10 carbon atoms, and having 2 to 10 carbon atoms. -alkynyl or C 3-7 -cycloalkyl, each with. He said. an aliphatic group may be optionally substituted with 1 or 2 substituents independently selected from the following: A compound of formula (I-a) according to claim 1, wherein R * is hydrogen or C 1-6 alkylcyclic, aryl, formyl, alkyl having 1 to 6 carbon atoms in the dummy part. C 1-6 -alkoxycarbosyl or chloromethyl; C 1-6 -alkylalkyl; or alkoxy-C 1-6 -alkyl substituted with 1-6 carbon atoms in the alkyl moiety. A compound of formula (I-a) according to claim 1 or claim 2, wherein L is -X-R-, wherein R- 'is phenyl substituted at the 2-, 4- and 6-positions. C-C 1 -C 7 -alkyl; mdolyl or isoindolyl, each of which may be optionally substituted with one, two, three or four substituents independently selected from the group consisting of balogene or C 1-6 -alkoxy, hydroxy, C 1-6 -alkoxy, cyano; . amiaocarbond, nitro, <RTI ID = 0.0> nitric, </RTI> polytromalomethyl, polMemethoxy or alkyl containing 1 to 6 carbon atoms in the alkyl moiety; * phenyl, pyridioyl, pyrimidyl, pyrazinyl or pyridazinyl, each of the deep aromatic rings may be optionally substituted with one, two, bar or four or five substituents independently selected from the group consisting of -R and -R; Is a group of general formula ^J wherein R- is selected from the group consisting of phenyl, pyridine, pyrimidinyl, pyrazinyl, and pyridazine, each of which is optionally substituted with aromatic rings. it may have one, two, three, four or five substituents independently selected from the one in its Statement; and X is -NR ¹ -, -NTI-NI-, -NN-, -O-, 47 (-O) -, -CHOH-, -S-, -S (- ^: 0) - or -St-6). ? - group ;. Q is a hydrogen or halogen atom or a C 1 -C 6 -alkyl, p-halogen (C 1 -C 6) -alkyl or - group; R ¹ and R ⁵ are independently hydrogen or hydroxy, C 1 -C 12 alkd, C 1 -C 12 alkydxyl, aliphatic carbonyl containing 1 to 12 carbon atoms in the alkyl moiety, alkyl alkoxy in the alkyl moiety of 1 to 12 carbon atoms, aryl ··, amino, mono- or diacetamines containing 1 to 12 carbon atoms in the dummy or alkyl moieties, or mono- or dialkylammonkbonyl containing 1 to 12 carbon atoms in the alkyl moiety or alkyl moiety, each of said 1 to 12 carbon atoms being optionally substituted with one another. independently one or two substituents selected from the group consisting of hydroxy, alkoxy having 1 to 6 carbon atoms, hydroxyalkoxy having 1 to 6 carbon atoms in alkyl, alkoxycarbonyl, cyano and amino having 1 to 6 carbon atoms in alkyl. itmno-, ie: mono- or dladdlamino, polyhalomethyl, polyhalomethoxy, polyhalogen-methyl, -S (~ O) containing from 1 to 6 carbon atoms in the alkyl moiety or alkoxy moieties. _; E ^Ö ~, -NH-Sf-OjpRfo, -C (-öjR ⁶ -, -NH € (- ^: 0) H, -Ct> 0} NliNH 2 - »-N'HC (~ O >> R ^fe -, -Cf-NHtS ⁹ -, aryl- and Seven-substituted arsenic-substituted findings: or K ⁴ and R together form pyrrolidine, piperidinyl, mortemanyl, sidido or mono- or di (C 1 -C 12) alkylamino (C 1 -C 4) -alkylidene; Y is halogen; hydroxy; Cycloalkyl having from 3 to 7 carbon atoms; alkenyl having 2 carbon atoms optionally substituted by one or more halogen atoms; one or more halogen atoms optionally substituted with 2 to 6 carbon atoms. alkynyl; eiano- or 47 {~ O) K ^!! C 1-6 -alkyl substituted by general formula (I); C 1 -C 6 alkoxy: in the alkyl moiety. t-carbonyl containing t -6 carbon atoms; karbexiícsoport ;. eianoesoport; lipo group: amino group:-* 0 0 Φ Φ Χ * * «« tartalmazó * * * * tartalmazó tartalmazó tartalmazó 37 tartalmazó tartalmazó aik φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ 37 37 φφ 37 φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ φφ 37 37 37 37; poíihalogéametoxicsoport; ροΙΙΙκΰορέηΗϊοίΙΙttoesoport; -S (-O) _p R ⁶ -; -HH-SfeOlpR ⁶ · -; C-O) ^ NHC (-öiH-; -C (-O) NHNKr; NHC (O) R ⁶ -; • -C ^::: 'NH) R ^f5; or Chapter:; aryl is a phenyl group or one, two, Htom, four or xylstituents selected from the group consisting of fealogacatoms 1-6 carbon atoms; containing olefinic acid groupsSisl, C3-C7 cycloalkyl, C1-C6 alkoxy, cyano-deporte, Ni-oxo »the alkyl moiety contains a C 1-6 -alkyl polyhalogen or a C 1-6 -alkoxy-substituted or unsaturated polyhalo and Two are aliphatic or aromatic tertiary cyclic groups, with the aliphatic heterocyclic group being pyrrohdymyl, piperidinyl, homepiperidinyl, piperazinyl, n-mpholinyl, tethydrofutanoyl or tetrahydrohydrogen, each of which is an aliphatic heterocyclic moiety; and said aromatic heterocyclic group is pyrrolyl, finutyl, rienyl, pyridyl. pinimidimyl, pyrazimyl, or pyridazinyl, each of which is an aromatic heterocyclic group which may be optionally substituted by a hydroxyl group, an N-oxide, an addition salt thereof, and an anion number of a quaemer. or a stereochemically isomeric form thereof. 4. A compound of formula (I-a) according to claim 1, wherein Y is a halogen atom or a cyano or -C (-O) X1-Iy group. 5. One that is. 1-4. A compound of formula (I-a) according to any one of claims 1 to 3 wherein Q is hydrogen or -NR 1 R 5. 6. The formula (I-a) according to any one of claims 1 to 3. which is 4 - [[4-stnbso * 5-chloro-6 - [(2,4,6-trimethyl) methyl] -2-piperimidoylamino] -butizonitrile 4-r [5-chloro-4- [2,2,6-trimethylphenyl]. amino) -2-pirimidiaiilaminoibenzonitrii; 4- [i5 brónv4- (4 ~ oiano-2, O-íhmerilfersuxÍ) -2-pirimidiníljammo] beuzönitril; 4-1 (4-Amino-5-chloro-6-IX-4-yloo-2,8-dimethylmethyl) -amyl-2-pyridylmethyl-olefin-4-cyano-2 (4-cyano-2) , 6-dimethylenyl) anmoyl-2-pyridinylamidol-2-yl-benzothiophene; 4- {4,3-tritro-5-chloro-6- (4-cyano-2,6-dimethyldimethoxy) -2-pyrimidine Hammool- benzomtric or 4 - [(4-aniloyl-5-yniris-6- (4-cyano) -2,6-dimethylphenoxy] -2-pyrimidin-5-yl] -ammonobonitrile, and. their N-oxides, addition salts, quaternary atnine derivatives and. isomeric isomeric forms. A compound according to claim 6, which is 4-i (4-amo-5-bromo-6- (4-clano-2-o-dimethylmethyl-oxo-d-pyrimidinyl) -nojbeazouitrile and is M- oxide and its addition salt, 8. One of claims 1-7. A compound according to any one of claims 1 to 6 for sublingualization as a drug. A compound of formula t i - - where n is 1, 2, 3,4 or 5, R *, KA, L, Q, and Y are as defined in claim 1, wherein the pharmaceutically acceptable addition salt, quaternary amine derivative or stereochemically isomeric compound is used for the treatment of infections caused by 1-11V (Boomean virus deficient virus). for the preparation of pharmaceutical preparations. Shoot. 1-7. Use of a compound according to any one of claims 1 to 6 for the manufacture of a medicament for the treatment of infections caused by the human immunoglobulin virus. Use of a compound according to any one of claims 1 to 7 according to claims 1-7. For the preparation of a pharmaceutical composition for the treatment of HIV-1 infection which is resistant to a non-mkleose reverse transcriptase inhibitor as defined in claims 1 to 4. 12. A compound according to any one of claims 1 to 5, from needle R * is hydrogen. or aryl, boiling, in the dummy part, containing 1 to 6 carbon atoms in the dummy, 1 to 6 carbon atoms in the alkyl moiety, 1 to 6 carbon atoms in the alkyl moiety, 1 to 6 carbon atoms in the alkyl moiety, Use of a C 1-6 alkyl group substituted by a -6-carbon alkoxymethylbonyl moiety - HIV (Human Hemetrelovirus) et ·· rd · '<; .P4 j, y, · <ΐ. 13. A pharmaceutical composition comprising a therapeutically effective amount of azf-7 as an active ingredient. contains a compound according to any one of claims 1 to 7, commonly used in pharmaceuticals together with excipients and / or other excipients. A process for the preparation of a pharmaceutical composition according to claim 13, characterized in that a therapeutically effective amount of a compound according to any one of claims 1 to 7 is intimately mixed with a pharmaceutical carrier conventionally used in the manufacture of pharmaceuticals. 15. A process for the preparation of a compound according to claim 1, characterized in that a): a compound of one of the general images of Il (II). wherein W * is a suitable leaving group, wherein L, Y, Q, R 1, R 4 R 4 and o are as defined in claim 1, under solvent-free conditions or in a solvent-inert atmosphere, or b) a compound of general formula (IV) with a compound of general formula (V) .. Υ) - wherein W ² is a suitable leaving group, while Y, Q, R ^! , R ² , R ^2s , R ^J and q are as defined in claim I - are reacted under solvent-free conditions or in a suitable solvent under an inert atmosphere to give a compound of formula (IVt) with a compound of formula (Vit - in the formulas, W- is a suitable leaving group, while Y, Q, R ^{; , R ² . S ² ®, R and q are as defined in claim 1 in a suitable solvent in a boiling atmosphere in the presence of a suitable base. and optionally converting a reactive group of a compound of formula (I-a) thus obtained into another reactive group in a known manner and / or converting the compound of formula (I-a) thus obtained into an acid addition salt or the like; from the acid addition salt, the corresponding free base is liberated by treatment with alkali and, if desired, stereochemically isomeric forms are prepared. A combination of a compound according to claim 1 or 9 and another anti-retroviral compound. 17. The drug according to claim 16 is drug-containing. A pharmaceutical composition for simultaneous, separate or sequential anti-IFI treatment comprising (a) a compound according to claim I or 9 and (b) another anbreiroviral compound. 19. A pharmaceutical composition comprising (a) a compound according to claim 1 or 9 and (bi another anurettoviral compound) together with a carrier and / or other excipients commonly used in the manufacture of a medicament.